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4rz8

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Revision as of 07:12, 30 September 2015

Crystal structure of HIV-1 gp120 core in complex with NBD-11021, a small molecule CD4-antagonist

Structural highlights

4rz8 is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

Function

[Q0ED31_9HIV1] The envelope glyprotein gp160 precursor down-modulates cell surface CD4 antigen by interacting with it in the endoplasmic reticulum and blocking its transport to the cell surface (By similarity).[RuleBase:RU004292][SAAS:SAAS000328_004_020447] The gp120-gp41 heterodimer allows rapid transcytosis of the virus through CD4 negative cells such as simple epithelial monolayers of the intestinal, rectal and endocervical epithelial barriers. Both gp120 and gp41 specifically recognize glycosphingolipids galactosyl-ceramide (GalCer) or 3' sulfo-galactosyl-ceramide (GalS) present in the lipid rafts structures of epithelial cells. Binding to these alternative receptors allows the rapid transcytosis of the virus through the epithelial cells. This transcytotic vesicle-mediated transport of virions from the apical side to the basolateral side of the epithelial cells does not involve infection of the cells themselves (By similarity).

Publication Abstract from PubMed

Earlier we reported the discovery and design of NBD-556 and their analogs which demonstrated their potential as HIV-1 entry inhibitors. However, progress in developing these inhibitors has been stymied by their CD4-agonist properties, an unfavorable trait for use as drug. Here, we demonstrate the successful conversion of a full CD4-agonist (NBD-556) through a partial CD4-agonist (NBD-09027), to a full CD4-antagonist (NBD-11021) by structure-based modification of the critical oxalamide midregion, previously thought to be intolerant of modification. NBD-11021 showed unprecedented neutralization breath for this class of inhibitors, with pan-neutralization against a panel of 56 Env-pseudotyped HIV-1 representing diverse subtypes of clinical isolates (IC50 as low as 270 nM). The cocrystal structure of NBD-11021 complexed to a monomeric HIV-1 gp120 core revealed its detail binding characteristics. The study is expected to provide a framework for further development of NBD series as HIV-1 entry inhibitors for clinical application against AIDS.

Structure-Based Design of a Small Molecule CD4-Antagonist with Broad Spectrum Anti-HIV-1 Activity.,Curreli F, Kwon YD, Zhang H, Scacalossi D, Belov DS, Tikhonov AA, Andreev IA, Altieri A, Kurkin AV, Kwong PD, Debnath AK J Med Chem. 2015 Aug 28. PMID:26301736^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Curreli F, Kwon YD, Zhang H, Scacalossi D, Belov DS, Tikhonov AA, Andreev IA, Altieri A, Kurkin AV, Kwong PD, Debnath AK. Structure-Based Design of a Small Molecule CD4-Antagonist with Broad Spectrum Anti-HIV-1 Activity. J Med Chem. 2015 Aug 28. PMID:26301736 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00709

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4rz8"

@@ Line 4: / Line 4: @@
 <table><tr><td colspan='2'>[[4rz8]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RZ8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RZ8 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3ZM:5-(4-CHLOROPHENYL)-N-{(S)-[5-(HYDROXYMETHYL)-4-METHYL-1,3-THIAZOL-2-YL][(2R)-PIPERIDIN-2-YL]METHYL}-1H-PYRROLE-2-CARBOXAMIDE'>3ZM</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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=4rz8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rz8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4rz8 RCSB], [http://www.ebi.ac.uk/pdbsum/4rz8 PDBsum]</span></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=4rz8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rz8 OCA], [http://pdbe.org/4rz8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rz8 RCSB], [http://www.ebi.ac.uk/pdbsum/4rz8 PDBsum]</span></td></tr>
 </table>
 == Function ==
@@ Line 16: / Line 16: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4rz8" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4rz8

From Proteopedia

Revision as of 07:12, 30 September 2015

Crystal structure of HIV-1 gp120 core in complex with NBD-11021, a small molecule CD4-antagonist

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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