5kjr: Difference between revisions
m Protected "5kjr" [edit=sysop:move=sysop] |
No edit summary |
||
| Line 1: | Line 1: | ||
==Crystal structure of the ADCC-potent antibody N60-i3 Fab in complex with HIV-1 Clade A/E gp120 W69A/S115W mutant and M48U1.== | |||
<StructureSection load='5kjr' size='340' side='right' caption='[[5kjr]], [[Resolution|resolution]] 2.98Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5kjr]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KJR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KJR FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | |||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=DPR:D-PROLINE'>DPR</scene>, <scene name='pdbligand=MPT:BETA-MERCAPTOPROPIONIC+ACID'>MPT</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=U2X:O-(CYCLOHEXYLMETHYL)-L-TYROSINE'>U2X</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4rfo|4rfo]]</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5kjr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kjr OCA], [http://pdbe.org/5kjr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kjr RCSB], [http://www.ebi.ac.uk/pdbsum/5kjr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kjr ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Previous studies have shown that highly-conserved residues in the inner domain of the gp120 are required for HIV-1 envelope glycoproteins (Env) transitions to the CD4-bound conformation. Moreover, W69, a highly conserved residue located at the interface between Layer 1 and Layer 2 of the inner domain, was recently shown to be important for efficient Env recognition by CD4-induced (CD4i) antibodies capable of potent antibody-dependent cellular cytotoxicity. We evaluated the contribution of the hydrophobicity of W69 on conformational changes of Env by replacing it with a series of residues with aliphatic or aromatic side chains of decreasing chain length. We have found that the hydrophobicity of residue 69 is important for Env processing, CD4 binding and its transition to the CD4-bound conformation. The most deleterious effect was observed when W69 was replaced by alanine or glycine residues. However, the functions lost due to W69 mutations could be progressively restored with amino acids of increasing aliphatic chain length and fully recovered with residue bearing an aromatic ring.Interestingly, poor CD4 binding of W69A could be fully restored by introducing a compensatory mutation within Layer 2 (S115W). Structural studies of HIV-1 gp120 coree W69A/S115W mutant bound to the CD4 peptide mimetic M48U1 and Fab of anti-Cluster A antibody N60-i3 revealed no perturbations to the overall structure of the double mutant as compared to the wild type protein but identified higher mobility within the interface between Layer 1 and Layer 2, the bridging sheet region and the CD4 binding site. IMPORTANCE: HIV-1 Env transitions to the CD4-bound conformation are required for viral entry. Previous studies identified a highly-conserved residue of the inner domain, W69, as being involved in these conformational transitions. Here, we show that W69, located at the interface between the gp120 and the gp41 in the PGT151-bound trimer, plays a critical role in the inter-protomer signaling induced by CD4 binding. This new information might be useful in immunogen design. | |||
A Highly Conserved gp120 Inner Domain Residue Modulates Env Conformation and Trimer Stability.,Ding S, Tolbert WD, Prevost J, Pacheco B, Coutu M, Debbeche O, Xiang SH, Pazgier M, Finzi A J Virol. 2016 Jul 6. pii: JVI.01068-16. PMID:27384653<ref>PMID:27384653</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5kjr" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Pazgier, M]] | [[Category: Pazgier, M]] | ||
[[Category: Tolbert, W | [[Category: Tolbert, W D]] | ||
[[Category: Clade a/e 93th057]] | |||
[[Category: Hiv-1 gp120]] | |||
[[Category: Viral protein]] | |||
[[Category: Viral protein-immune system-inhibitor complex]] | |||
Revision as of 18:12, 26 July 2016
Crystal structure of the ADCC-potent antibody N60-i3 Fab in complex with HIV-1 Clade A/E gp120 W69A/S115W mutant and M48U1.Crystal structure of the ADCC-potent antibody N60-i3 Fab in complex with HIV-1 Clade A/E gp120 W69A/S115W mutant and M48U1.
Structural highlights
Publication Abstract from PubMedPrevious studies have shown that highly-conserved residues in the inner domain of the gp120 are required for HIV-1 envelope glycoproteins (Env) transitions to the CD4-bound conformation. Moreover, W69, a highly conserved residue located at the interface between Layer 1 and Layer 2 of the inner domain, was recently shown to be important for efficient Env recognition by CD4-induced (CD4i) antibodies capable of potent antibody-dependent cellular cytotoxicity. We evaluated the contribution of the hydrophobicity of W69 on conformational changes of Env by replacing it with a series of residues with aliphatic or aromatic side chains of decreasing chain length. We have found that the hydrophobicity of residue 69 is important for Env processing, CD4 binding and its transition to the CD4-bound conformation. The most deleterious effect was observed when W69 was replaced by alanine or glycine residues. However, the functions lost due to W69 mutations could be progressively restored with amino acids of increasing aliphatic chain length and fully recovered with residue bearing an aromatic ring.Interestingly, poor CD4 binding of W69A could be fully restored by introducing a compensatory mutation within Layer 2 (S115W). Structural studies of HIV-1 gp120 coree W69A/S115W mutant bound to the CD4 peptide mimetic M48U1 and Fab of anti-Cluster A antibody N60-i3 revealed no perturbations to the overall structure of the double mutant as compared to the wild type protein but identified higher mobility within the interface between Layer 1 and Layer 2, the bridging sheet region and the CD4 binding site. IMPORTANCE: HIV-1 Env transitions to the CD4-bound conformation are required for viral entry. Previous studies identified a highly-conserved residue of the inner domain, W69, as being involved in these conformational transitions. Here, we show that W69, located at the interface between the gp120 and the gp41 in the PGT151-bound trimer, plays a critical role in the inter-protomer signaling induced by CD4 binding. This new information might be useful in immunogen design. A Highly Conserved gp120 Inner Domain Residue Modulates Env Conformation and Trimer Stability.,Ding S, Tolbert WD, Prevost J, Pacheco B, Coutu M, Debbeche O, Xiang SH, Pazgier M, Finzi A J Virol. 2016 Jul 6. pii: JVI.01068-16. PMID:27384653[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||||