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"Finally,Structure of free and ISG15-bound USP18 (A) Overall structure of USP18 (pdb code 5cht) showing the three-domain architecture with finger, thumb and palm domains."

No evidence text available

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"Since the interaction surfaces in the USP18ISG15 complex are well conserved between human and murine proteins, we tested whether the ISG15-PA active site probes label USP18 across species."

sparser
"Multiple structural alignment was performed using the Dali server47 and the coordinates of the USP18ISG15 complex as search model."

sparser
"There are two USP18ISG15 complexes in the asymmetric unit."

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"In both molecules of unbound USP18 the imidazole of His314 is slightly shifted away from Cys61 weakening the interaction of the two side chains.Figure 2: (a) Structural alignment of both USP18ISG15 complexes present in the asymmetric unit."

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"Therefore, the α-helix must unwind and the loop needs to change its conformation to allow for ISG15 binding.Finally, the catalytic triad in ISG15-bound USP18 is formed by small movements of all three residues (His314, Asn331, Cys61) involved (Fig. 1b-d)."

sparser
"Mechanistic studies demonstrated that ISG15 binds to and stabilizes USP18 by preventing its ubiquitylation by S-phase kinase-associated protein 2 (SKP2) 4 ( fig."

sparser
"Structure of USP18 in the unbound and ISG15-bound state (a) USP18 crystallized with two molecules in the asymmetric unit."

sparser
"In humans, ISG15 binds to USP18, increasing its stability and leading to a decrease in IFN-α/β signaling."

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"Alignment of the unbound USP18 molecules with the ISG15 bound USP18 revealed substantial structural differences."

sparser
"523 Protection associated with the induction of a superior ISG response in HNFL mice as 524 compared to NRG-L mice, which was dominated by the upregulation of the USP18-ISG15 axis -525 a unique feature of inoculated HNFL fLX."
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"For the structure of the USP18ISG15 complex the structures of unbound USP18 and murine ISG15 were used as search model in molecular replacement trials with Phaser."

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"(a) Structure of the USP18-ISG15 complex."

sparser
"As such, the USP18:ISG15 interaction is a potentially attractive target for small molecule-based short-term treatments to boost endogenous IFN activity."

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"The following structures were compared with USP18: USP7 (PDB code 1NBF, chain B)40, USP21 (PDB code 2Y5B, chain A)27, USP2 (PDB code 2IBI, chain A), USP14 (PDB code 2AYN, chain A)42, USP8 (PDB code 3N3K, chain A)70, USP4 (PDB code 2Y6E, chain B)71, USP5 (PDB code 3IHP, chain A)72, SARS CoV PLpro (PDB code 5E6J, chain A)46.Coordinates and structure factors for USP18 and USP18ISG15 complex were deposited at the protein database under accession code 5CHT and 5CHV, respectively.Figure 1: (a) USP18 crystallized with two molecules in the asymmetric unit."

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"The interaction of murine USP18 and ISG15 as well as of several variants was analyzed by surface plasmon resonance (SPR)."

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"In human cells, binding of ISG15 to USP18 increases USP18 levels by preventing its degradation [29] , further reinforcing the inhibition of IFN receptor signaling."

sparser
"While a crystal structure of mouse USP18ISG15 has been utilized to account for the specificity of ISG15 over Ub, analyses have yet to be performed that clearly determine the cause for the differences in USP18ISG15 interactions between humans and mice [59], [60]."

sparser
"The USP18ISG15 complex was used at a concentration of 5 mg ml-1 for crystallization."

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"Thus, our results demonstrate that only the C-terminal Ubl domain of ISG15 is essential and sufficient for USP18 binding and activity.Alignment of the unbound USP18 molecules with the ISG15-bound USP18 revealed substantial structural differences."

sparser
"The ISG15-binding boxes 1 (IBB-1) and 2 (IBB-2) of USP18 are depicted in green and purple, respectively. (b) Structural alignment of the USP18ISG15 complex with the USP7–Ub complex (PDB code 1NBF)40."

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"A similar experiment was conducted making use of the equivalent propargylamide probe, ISG15-PRG, with USP18-ISG15 complex formation."

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"Mechanistic studies demonstrated that ISG15 binds to and stabilizes USP18 by preventing its ubiquitylation by S-phase kinase-associated protein 2 (SKP2)4 (Fig. 2)."

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"Overall structure of the USP18 and ISG15 complex."

sparser
"Mechanistic studies demonstrated that ISG15 binds to and stabilizes USP18 by preventing its ubiquitylation by S-phase kinase-associated protein 2 (SKP2)4 (Fig. 2)."

sparser
"ISG15-VS results in the formation of a covalent complex between USP18 and ISG15."

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"Likewise, the so-called switching loop in the thumb domain of USP18 occured in an inactive or an active conformation that allows or prevents ISG15 binding, respectively.The structure of an USP18ISG15 complex revealed the catalytically active conformation of USP18 [35]."

sparser
"Non-conjugated ISG15 binds and stabilises USP18. (4) Inhibition of proteasomal degradation."

sparser
"Since the interaction surfaces in the USP18ISG15 complex are well conserved between human and murine proteins, we tested whether the ISG15-PA active site probes label USP18 across species."

sparser
"The pronounced upregulation of the USP18-ISG15 axis (a negative regulator of IFN responses), by macrophages was unique to HNFL mice and represented a prominent correlate of reduced inflammation and histopathology."
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sparser
"In human cells, binding of ISG15 to USP18 increases USP18 levels by preventing its degradation [29] , further reinforcing the inhibition of IFN receptor signaling."

sparser
"The overall structures of USP–Ub complexes and the USP18ISG15 complex are remarkably similar (Fig. 4a,b) and as shown here only the C-terminal Ubl domain of ISG15 is required for binding."

sparser
"The observations for the ISG15 variants corroborated the structural data showing that IBB-1 represents an important determinant for the interaction between USP18 and ISG15."

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"In order to identify critical residues, we performed a Dali search XREF_BIBR with the structure of ISG15 bound USP18 defining USP2, USP4, USP5, USP7, USP8, USP14 and USP21 as closest homologues."

No evidence text available

sparser
"We have shown that free ISG15 associates with higher affinity to USP18 in humans as compared with mice, although the species-specific structural determinants involved in complex formation have yet to be identified."

sparser
"Superposition of the two chains present in the asymmetric unit revealed that the enzyme had crystallised in two conformations that mainly differ in the orientation of the finger domain. (B) Structure of the USP18ISG15 complex (pdb code 5chv)."

sparser
"To gain insights into the mechanism of recognition and catalysis by USP18 we have determined structures of murine USP18 and of a complex of murine USP18 with murine ISG15 by X-ray crystallography."

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"The orientation of Ub bound to USP7 closely resembles the orientation of the ISG15 C-terminal domain in the USP18ISG15 complex."

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"For comparison ISG15-bound USP18 (light blue) is structurally aligned."

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"To evaluate whether human USP18 recognizes ISG15 like murine USP18, we built a 3D model of the human USP18 and ISG15 complex based on the structure of the murine USP18 and ISG15 complex."

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"The structure of unbound USP18 was solved by molecular replacement with Phaser64 using USP7 (PDB code 1NB8) as search model.For the structure of the USP18-ISG15 complex the structures of unbound USP18 and murine ISG15 were used as search model in molecular replacement trials with Phaser."

sparser
"In ISG15-bound USP18 the α-helix unwinds and the entire loop comprising these residues is displaced."

sparser
"Finally, the catalytic triad in ISG15-bound USP18 is formed by small movements of all three residues (His314, Asn331, Cys61) involved ( xref )."

sparser
"Bulk transcriptomic analysis of HNFL fLX at 442 2DPI confirmed significant upregulation of the USP18-ISG15 axis (FDR=6.69e-235 and 0, 443 respectively), as well as the strong upregulation of many other ISGs such as RSAD2, IFI44/L, 444 OAS1, MX1-2, IFI6, LYE6 (FDR=0) (Figure 5V)."
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sparser
"Protective IFN response was dominated by the upregulation of the USP18-ISG15 axis."
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sparser
"USP18-ISG15 upregulation correlated with the absence 526 of prolonged inflammation and severe histopathology, consistent with its role as a negative 527 regulator of antiviral responses."
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"A striking and specific feature 433 of the proteomic response in HNFL fLX was that it was dominated by the upregulation of the 434 USP18-ISG15 axis, unlike NRG-L fLX, which did not display any significant USP18 upregulation 435 (Figure 5T-U)."
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"(b) Structural alignment of the USP18ISG15 complex with the USP7–Ub complex (PDB code 1NBF)40."

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"In human cells, binding of ISG15 to USP18 increases USP18 levels by preventing its degradation XREF_BIBR, further reinforcing the inhibition of IFN receptor signaling."

sparser
"Finally, the catalytic triad in ISG15-bound USP18 is formed by small movements of all three residues (His314, Asn331, Cys61) involved (Fig. 1b-d)."

sparser
"A similar experiment was conducted making use of the equivalent propargylamide probe, ISG15-PRG, with USP18-ISG15 complex formation."

No evidence text available

sparser
"Data for the USP18ISG15 were collected at 100 K with a wavelength of 1.0 Å at beamline X06DA, Swiss Light Source, equipped with a PILATUS 2M detector."

sparser
"Upregulation of the USP18-ISG15 axis allows for a tightly balanced inflammatory response that 887 preserves lung tissue integrity during the antiviral response (4)."
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sparser
"In contrast, in a recent study it was concluded that the mode of USP18ISG15 interaction might differ between murine and human proteins51."

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"Furthermore, we demonstrate that there is a species specific interaction between ISG15 and USP18."

sparser
"Given the human specific nature of the interaction between 611 USP18 and ISG15 (Speer et al., 2016), the HNFL model uniquely positions itself for such 612 investigation over other animal models of SARS-CoV-2 infection."
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sparser
"It was shown that ISGylation-defective ΔGG ISG15 also binds to USP18 and prevents its degradation24."

sparser
"However, besides the classical biochemical protease assay where recombinant USP18 is used in combination with ISG15-TAMRA (Basters et al., 2014), a screening system suitable to monitor direct USP18-ISG15 binding could be helpful."

sparser
"The orientation of Ub bound to USP7 closely resembles the orientation of the ISG15 C-terminal domain in the USP18ISG15 complex. (c) Close-up view of ISG15-binding box 1 (IBB-1)."

sparser
"In contrast, in a recent study it was concluded that the mode of USP18ISG15 interaction might differ between murine and human proteins xref ."

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"The structure of the USP18ISG15 complex described below, revealed that the closed state of USP18 is not compatible with ISG15 binding."

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"An extensive network of hydrogen bonds mediate the interaction between ISG15 and USP18."

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"There are two USP18ISG15 complexes in the asymmetric unit."

sparser
"Furthermore, we demonstrate that there is a species-specific interaction between ISG15 and USP18."

sparser
"ISG15 bound to immobilized USP18 with high affinity characterized by a fast association and dissociation phase."

sparser
"Activated macrophage (AM) clusters are indicated 863 (clusters 9, inflammatory macrophages; cluster 10, regulatory macrophages) 864 L. Differential co-expression of the USP18-ISG15 axis across human lineages in infected fLX."
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"A molecular model of a USP18ISG15 complex carrying these mutations suggested that the side chains of these polar residues can form several hydrogen bonds."

sparser
"In ISG15-bound USP18, residues 129-135 of the thumb domain form an extended loop."

sparser
"By identifying a distinct hydrophobic patch critical for ISG15USP18 recognition, this study shows that even small changes on the surface are sufficient to generate a highly specific enzyme capable to distinguish between ubiquitin and the structurally related Ubl domain of ISG15."

sparser
"The structure of an USP18ISG15 complex revealed the catalytically active conformation of USP18 [35]."

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"Our findings 534 provide unique molecular correlates of lung tissue protection during SARS-CoV-2 infection, and 535 propose a unique model in which macrophage-mediated ISG responses would promote a 536 systemic antiviral response against SARS-CoV-2, and tight control of these responses via the 537 USP18-ISG15 axis would prevent excessive inflammation and severe histopathology."
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sparser
"For comparison ISG15-bound USP18 (light blue) is structurally aligned."

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"(B) Structure of the USP18ISG15 complex (pdb code 5chv)."

sparser
"Based on the structure of USP21 in complex with di-ubiquitin it had been suggested that USP18 binds ISG15 in a similar mode."

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"Finally, the catalytic triad in ISG15 bound USP18 is formed by small movements of all three residues (His314, Asn331, Cys61) involved (XREF_FIG)."

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"This mode of binding closely resembles the interaction of ubiquitin with other USPs like USP740.The comparison of both USP18ISG15 complexes in the asymmetric unit revealed that the C-terminal Ubl domains of ISG15 align with high similarity (r.m.s.d."

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"Given the human specific nature of the interaction between 611 USP18 and ISG15 (Speer et al., 2016), the HNFL model uniquely positions itself for such 612 investigation over other animal models of SARS-CoV-2 infection."
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sparser
"Coordinates and structure factors for USP18 and USP18ISG15 complex were deposited at the protein database under accession code 5CHT and 5CHV, respectively."

sparser
"It was shown that ISGylation-defective ΔGG ISG15 also binds to USP18 and prevents its degradation xref ."

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"For example, in humans (but not mice), ISG15 interacts with and stabilizes USP18, allowing for appropriate downregulation of IFN signalling67."

sparser
"Alignment of the unbound USP18 molecules with the ISG15-bound USP18 revealed substantial structural differences."

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"The distances between ubiquitin and USP7 are larger than in the USP18-ISG15 complex."

reach
"The overall structures of USP–Ub complexes and the USP18ISG15 complex are remarkably similar (Fig. 4a,b) and as shown here only the C-terminal Ubl domain of ISG15 is required for binding."

reach
"Figures of the structures were prepared with Pymol68.Multiple structural alignment was performed using the Dali server47 and the coordinates of the USP18ISG15 complex as search model."

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"The hydrophobic nature of Box1 and of the USP18ISG15 interaction plane suggests that a similar mode of interaction might occur between USP18 and IFNAR2.In summary, here we unravel the molecular properties that determine the unique specificity of USP18."

sparser
"USP18 also has enzymatic activity in removing the covalently conjugated 15kDa protein, encoded by interferon-stimulated gene 15 ( ISG15 ), from its targets in a process called de-ISGylation. xref Finally, independent of its affinity for ISGylated proteins, USP18 also binds free ISG15, which protects USP18 against proteasomal degradation, thereby enhancing its negative regulatory capacity. xref "

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"Further work is required to identify the domain(s) responsible for the human ISG15:USP18 interactions that are required to enhance stability and properly regulate the IFN responses."

sparser
"Figure 2: (a) Structural alignment of both USP18ISG15 complexes present in the asymmetric unit."

sparser
"The structure of the USP18ISG15 complex described below, revealed that the closed state of USP18 is not compatible with ISG15 binding."

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"The overall structures of USP-Ub complexes and the USP18 and ISG15 complex are remarkably similar (XREF_FIG) and as shown here only the C-terminal Ubl domain of ISG15 is required for binding."

sparser
"The interaction between USP18 and ISG15 is mediated by hydrophobic residues, whereas USP7 and ubiquitin display polar residues in this region. (e) Close-up view of IBB-2 (purple)."

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"Intriguingly, human free ISG15 is needed to bind and stabilize the USP18 negative regulator, independent of ISG15 conjugation (ISGylation) [ xref ]."

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"The structures of USP18 and a USP18 and ISG15 complex revealed the molecular basis of the unique specificity of the protease and might shed some light into its interaction with the interferon receptor."

sparser
"These investigators also found that murine ISG15 does not bind USP18, and hence does not downregulate IFN-a/b signalling in mice."

sparser
"The covalent complex of murine USP18 with murine ISG15 was prepared using ISG15 modified with a C-terminal propargylamide (PA) reactive group (ISG15-PA) 45."

sparser
"Figure 3: Structural alignment of USP18 (light blue) bound to ISG15 (orange) and unbound USP18 (dark blue) reveals a conformational change in the finger domain as well as in the blocking and switching loops. (a) Residues 255-267 (blocking loop 1) that are unordered in unbound USP18 fold into a short β-sheet that interacts with ISG15. (b) The switching loop connects helix 4 and helix 5 of the thumb domain and comprises residues 129-135."

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"As macrophage-mediated inflammation has been suggested by many human 599 studies to contribute to COVID-19 (Grant et al., 2021; Merad and Martin, 2020; Rendeiro et al., 600 2021; Wauters et al., 2021), and the USP18-ISG15 axis is not upregulated in NRG-L mice, our 601 data imply that upregulation of the USP18-ISG15 axis acts as an important regulator of 602 macrophage inflammation during infection, keeping positive inflammatory feedback loops in 603 check (e.g., via the downregulation of RIG-I-mediated signaling, for instance) in order to prevent 604 excessive tissue damage during host-mediated antiviral responses."
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sparser
"The interaction of murine USP18 and ISG15 as well as of several variants was analyzed by surface plasmon resonance (SPR)."

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"(b-d) Close-up view of the catalytic triad in unbound and ISG15-bound USP18."

sparser
"For the structure of the USP18ISG15 complex the structures of unbound USP18 and murine ISG15 were used as search model in molecular replacement trials with Phaser."

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"(b) Only in ISG15-bound USP18 the side chains of the three residues exhibit the correct orientation and distances to stabilize a thiolate state of the Sγ of Cys61."

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"In order to identify critical residues, we performed a Dali search47 with the structure of ISG15-bound USP18 defining USP2, USP4, USP5, USP7, USP8, USP14 and USP21 as closest homologues."

sparser
"A structural overlay of unbound USP18 and the USP18ISG15 complex reveals that residues Arg151 and Arg153 of the LRLRGG motif clash with this short α-helix of unbound USP18 (Fig. 3b)."

sparser
"ISG15 deficiency caused increased viral resistance in humans but not mice, since only human ISG15 interacted with USP18 and decreased the response to IFN-α25."

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"Residues 255-267 corresponding to blocking loop 1 are unordered in unbound USP18 and not resolved in the electron density, whereas they form a short antiparallel β sheet in ISG15-bound USP18 . (b-d) Close-up view of the catalytic triad in unbound and ISG15-bound USP18."

sparser
"Importantly, activated 494 macrophages also represented the dominant source of USP18-ISG15 co-expression (Figure 6L) 495 strengthening their key role in regulating antiviral responses during infection."
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sparser
"Notably, human ISG15 binds to USP18 and inhibits SKP2-mediated ubiquitylation and proteasomal-mediated degradation4,114."

sparser
"The comparison of both USP18ISG15 complexes in the asymmetric unit revealed that the C-terminal Ubl domains of ISG15 align with high similarity (r."

sparser
"Structural alignment of USP18 (light blue) bound to ISG15 (orange) and unbound USP18 (dark blue) reveals a conformational change in the finger domain as well as in the blocking and switching loops. (a) Residues 255-267 (blocking loop 1) that are unordered in unbound USP18 fold into a short β-sheet that interacts with ISG15. (b) The switching loop connects helix 4 and helix 5 of the thumb domain and comprises residues 129-135."

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"ISG15 deficiency caused increased viral resistance in humans but not mice, since only human ISG15 interacted with USP18 and decreased the response to IFN-alpha 25."

sparser
"588 A unique finding of our study is the strong association between the upregulation of the 589 USP18-ISG15 axis by macrophages and limited histopathology and inflammation."
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"The observations for the ISG15 variants corroborated the structural data showing that IBB-1 represents an important determinant for the interaction between USP18 and ISG15."

reach
"The interaction between USP18 and ISG15 is mediated by hydrophobic residues, whereas USP7 and ubiquitin display polar residues in this region."

sparser
"545 The USP18-ISG15 axis would tightly control those responses in order to protect the tissue from 546 excessive inflammation."
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sparser
"While a crystal structure of mouse USP18ISG15 has been utilized to account for the specificity of ISG15 over Ub, analyses have yet to be performed that clearly determine the cause for the differences in USP18ISG15 interactions between humans and mice xref , xref ."

sparser
"Data collection and refinement statistics are given in Table 1 Coordinates and structure factors for USP18 and USP18-ISG15 complex were deposited at the protein database under accession code 5CHT and 5CHV, respectively."

sparser
"ISG15 deficiency caused increased viral resistance in humans but not mice, since only human ISG15 interacted with USP18 and decreased the response to IFN-α xref ."

reach
"Multiple structural alignment was performed using the Dali server47 and the coordinates of the USP18-ISG15 complex as search model."

reach
"A subsequent analysis of cells derived from ISG15-deficient mice and humans demonstrated that, unlike human ISG15, which can bind to human uSP18 and prevent its ubiquitylation and subsequent SKP2-mediated degradation, mouse ISG15 was not able to stabilize uSP18 (ref."

No evidence text available

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"We recently demonstrated that human free intracellular ISG15 binds USP18, a negative regulator of IFN-alpha and beta signalling."

sparser
"In human cells, binding of ISG15 to USP18 increases USP18 levels by preventing its degradation xref , further reinforcing the inhibition of IFN receptor signaling."

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"The distances between ubiquitin and USP7 are larger than in the USP18ISG15 complex.Figure 5: (a) Wildtype USP18 and the different USP18 variants were incubated with ISG15- and ct-ISG15-PA probes for the indicated times."

sparser
"To evaluate whether human USP18 recognizes ISG15 like murine USP18, we built a 3D model of the human USP18ISG15 complex based on the structure of the murine USP18ISG15 complex."

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"Mechanistic studies demonstrated that ISG15 binds to and stabilizes USP18 by preventing its ubiquitylation by S-phase kinase-associated protein 2 (SKP2) 4 ( fig."

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"Notably, human ISG15 binds to USP18 and inhibits SKP2-mediated ubiquitylation and proteasomal-mediated degradation4,114."

sparser
"Besides, we described that the down-regulated genes in PAMs challenged by A1 possibly inhibits the interaction of ISG15 and USP18 as negative regulators of the immune response."

reach
"The structure of the USP18 and ISG15 complex described below, revealed that the closed state of USP18 is not compatible with ISG15 binding."

reach
"The USP18ISG15 complex was used at a concentration of 5 mg ml-1 for crystallization."

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"In ISG15-bound USP18 the α-helix unwinds and the entire loop comprising these residues is displaced.Nat Struct Mol Biol."

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"Based on the structure of USP21 in complex with di-ubiquitin it had been suggested that USP18 binds ISG15 in a similar mode."

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"This defect could be restored by either wild-type or non-conjugatable ISG15, implicating non-covalent interactions between ISG15 and USP18."

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"In ISG15-bound USP18 the α-helix unwinds and the entire loop comprising these residues is displaced.Figure 4: (a) Structure of the USP18ISG15 complex."

sparser
"We recently demonstrated that human free intracellular ISG15 binds USP18, a negative regulator of IFN-α/β signalling."

sparser
"Alanine at position 138, leucine at position 142 and histidine at position 251 residues within USP18 generate a hydrophobic pocket and with the aid of glutamine at position 139 and serine at position 192 residues, the three residues are involved in the formation of hydrophobic interactions with the hydrophobic patch of ISG15, suggesting that the preferential recognition and high specificity of USP18 toward ISG15 could be achieved by the hydrophobic interactions between USP18 and ISG15."

sparser
"In order to identify critical residues, we performed a Dali search xref with the structure of ISG15-bound USP18 defining USP2, USP4, USP5, USP7, USP8, USP14 and USP21 as closest homologues."

sparser
"Structural alignment of both USP18-ISG15 complexes present in the asymmetric unit."

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"Consistent with the function of the USP18-ISG15 axis, phospho-440 proteomic analysis confirmed that STAT1 was significantly phosphorylated in NRG-L, but not in 441 HNFL fLX (Figure S7G,H; Supplemental Item 7)."
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sparser
"80 The pronounced upregulation of the USP18-ISG15 axis (a negative regulator of IFN responses), 81 by macrophages was unique to HNFL mice and represented a prominent correlate of reduced 82 inflammation and histopathology."
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sparser
"An extensive network of hydrogen bonds mediate the interaction between ISG15 and USP18."

reach
"A molecular model of a USP18 and ISG15 complex carrying these mutations suggested that the side chains of these polar residues can form several hydrogen bonds."

sparser
"The hydrophobic nature of Box1 and of the USP18ISG15 interaction plane suggests that a similar mode of interaction might occur between USP18 and IFNAR2."

sparser
"In order to identify critical residues, we performed a Dali search47 with the structure of ISG15-bound USP18 defining USP2, USP4, USP5, USP7, USP8, USP14 and USP21 as closest homologues."

sparser
"The distances between ubiquitin and USP7 are larger than in the USP18ISG15 complex."

sparser
"IBB-1 but not IBB-2 is critical for ISG15 binding and activity of USP18."

sparser
"These investigators also found that murine ISG15 does not bind USP18, and hence does not downregulate IFN-α/β signalling in mice."

sparser
"Figure 4: (a) Structure of the USP18ISG15 complex."

reach
"In humans, ISG15 binds to USP18, increasing its stability and leading to a decrease in IFN-α/β signaling."

reach
"Residues 255-267 corresponding to blocking loop 1 are unordered in unbound USP18 and not resolved in the electron density, whereas they form a short antiparallel β sheet in ISG15-bound USP18 ."

sparser
"A molecular model of a USP18ISG15 complex carrying these mutations suggested that the side chains of these polar residues can form several hydrogen bonds."

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"Data collection and refinement statistics are given in Table 1 Coordinates and structure factors for USP18 and USP18-ISG15 complex were deposited at the protein database under accession code 5CHT and 5CHV, respectively.Refer to Web version on PubMed Central for supplementary material."

reach
"Since the interaction surfaces in the USP18 and ISG15 complex are well conserved between human and murine proteins, we tested whether the ISG15-PA active site probes label USP18 across species."

sparser
"54 • Protective IFN response was dominated by the upregulation of the USP18-ISG15 axis."
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"To evaluate whether human USP18 recognizes ISG15 like murine USP18, we built a 3D model of the human USP18ISG15 complex based on the structure of the murine USP18ISG15 complex."

sparser
"Regions forming the interface with ISG15 are noted by blue bars based on a mouse USP18-ISG15 X-ray crystal structure (PDB entry 5CHV). (TIF) S1 File."

sparser
"Conformational changes in USP18 upon ISG15 binding ISG15-binding boxes 1 and 2 in USP18. (a) Structure of the USP18-ISG15 complex."

sparser
"A subsequent analysis of cells derived from ISG15-deficient mice and humans demonstrated that, unlike human ISG15, which can bind to human uSP18 and prevent its ubiquitylation and subsequent SKP2-mediated degradation, mouse ISG15 was not able to stabilize uSP18 (ref."