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| | ==Crystal structure of clade A/E 93TH057 HIV-1 gp120 core in complex with NBD-10007== | | ==Crystal structure of clade A/E 93TH057 HIV-1 gp120 core in complex with NBD-10007== |
| - | <StructureSection load='4dkv' size='340' side='right' caption='[[4dkv]], [[Resolution|resolution]] 2.18Å' scene=''> | + | <StructureSection load='4dkv' size='340' side='right'caption='[[4dkv]], [[Resolution|resolution]] 2.18Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4dkv]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DKV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DKV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4dkv]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DKV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DKV FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0KW:N-(4-CHLOROPHENYL)-N-{(S)-[5-(2-HYDROXYETHYL)-4-METHYL-1,3-THIAZOL-2-YL][(2S)-PIPERIDIN-2-YL]METHYL}ETHANEDIAMIDE'>0KW</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> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1847Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4dku|4dku]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0KW:N-(4-CHLOROPHENYL)-N-{(S)-[5-(2-HYDROXYETHYL)-4-METHYL-1,3-THIAZOL-2-YL][(2S)-PIPERIDIN-2-YL]METHYL}ETHANEDIAMIDE'>0KW</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=4dkv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dkv OCA], [http://pdbe.org/4dkv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dkv RCSB], [http://www.ebi.ac.uk/pdbsum/4dkv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dkv ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4dkv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dkv OCA], [https://pdbe.org/4dkv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dkv RCSB], [https://www.ebi.ac.uk/pdbsum/4dkv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dkv ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/Q0ED31_9HIV1 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). | + | [https://www.uniprot.org/uniprot/A0A0M3KKW9_9HIV1 A0A0M3KKW9_9HIV1] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4dkv" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4dkv" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Gp120 3D structures|Gp120 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Debnath, A K]] | + | [[Category: Human immunodeficiency virus 1]] |
| - | [[Category: Kwon, Y D]] | + | [[Category: Large Structures]] |
| - | [[Category: Kwong, P D]] | + | [[Category: Debnath AK]] |
| - | [[Category: Cd4 mimic]] | + | [[Category: Kwon YD]] |
| - | [[Category: Clade a/e]] | + | [[Category: Kwong PD]] |
| - | [[Category: Hiv-1 gp120]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Nbd-10007]]
| + | |
| Structural highlights
Function
A0A0M3KKW9_9HIV1
Publication Abstract from PubMed
We previously identified two small-molecule CD4 mimetics--NBD-556 and NBD-557--and synthesized a series of NBD compounds that resulted in improved neutralization activity in a single-cycle HIV-1 infectivity assay. For the current investigation, we selected several of the most active compounds and assessed their antiviral activity on a panel of 53 reference HIV-1 Env pseudoviruses representing diverse clades of clinical isolates. The selected compounds inhibited tested clades with low-micromolar potencies. Mechanism studies indicated that they act as CD4 agonists, a potentially unfavorable therapeutic trait, in that they can bind to the gp120 envelope glycoprotein and initiate a similar physiological response as CD4. However, one of the compounds, NBD-09027, exhibited reduced agonist properties, in both functional and biophysical studies. To understand the binding mode of these inhibitors, we first generated HIV-1-resistant mutants, assessed their behavior with NBD compounds, and determined the X-ray structures of two inhibitors, NBD-09027 and NBD-10007, in complex with the HIV-1 gp120 core at approximately 2-A resolution. Both studies confirmed that the NBD compounds bind similarly to NBD-556 and NBD-557 by inserting their hydrophobic groups into the Phe43 cavity of gp120. The basic nitrogen of the piperidine ring is located in close proximity to D368 of gp120 but it does not form any H-bond or salt bridge, a likely explanation for their nonoptimal antagonist properties. The results reveal the structural and biological character of the NBD series of CD4 mimetics and identify ways to reduce their agonist properties and convert them to antagonists.
Binding mode characterization of NBD series CD4-mimetic HIV-1 entry inhibitors by X-ray structure and resistance study.,Curreli F, Kwon YD, Zhang H, Yang Y, Scacalossi D, Kwong PD, Debnath AK Antimicrob Agents Chemother. 2014 Sep;58(9):5478-91. doi: 10.1128/AAC.03339-14., Epub 2014 Jul 7. PMID:25001301[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Curreli F, Kwon YD, Zhang H, Yang Y, Scacalossi D, Kwong PD, Debnath AK. Binding mode characterization of NBD series CD4-mimetic HIV-1 entry inhibitors by X-ray structure and resistance study. Antimicrob Agents Chemother. 2014 Sep;58(9):5478-91. doi: 10.1128/AAC.03339-14., Epub 2014 Jul 7. PMID:25001301 doi:http://dx.doi.org/10.1128/AAC.03339-14
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