3gi5: Difference between revisions
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==Crystal structure of protease inhibitor, KB62 in complex with wild type HIV-1 protease== | ==Crystal structure of protease inhibitor, KB62 in complex with wild type HIV-1 protease== | ||
<StructureSection load='3gi5' size='340' side='right' caption='[[3gi5]], [[Resolution|resolution]] 1.80Å' scene=''> | <StructureSection load='3gi5' size='340' side='right'caption='[[3gi5]], [[Resolution|resolution]] 1.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3gi5]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3gi5]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/9hiv1 9hiv1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3GI5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3GI5 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=K62:(5S)-3-(3-ACETYLPHENYL)-N-[(1S,2R)-3-[(1,3-BENZODIOXOL-5-YLSULFONYL)(2-METHYLPROPYL)AMINO]-2-HYDROXY-1-(PHENYLMETHYL)PROPYL]-2-OXO-5-OXAZOLIDINECARBOXAMIDE'>K62</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K62:(5S)-3-(3-ACETYLPHENYL)-N-[(1S,2R)-3-[(1,3-BENZODIOXOL-5-YLSULFONYL)(2-METHYLPROPYL)AMINO]-2-HYDROXY-1-(PHENYLMETHYL)PROPYL]-2-OXO-5-OXAZOLIDINECARBOXAMIDE'>K62</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3gi4|3gi4]], [[3gi6|3gi6]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3gi4|3gi4]], [[3gi6|3gi6]]</div></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">pol ([ | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">pol ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 9HIV1])</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3gi5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3gi5 OCA], [https://pdbe.org/3gi5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3gi5 RCSB], [https://www.ebi.ac.uk/pdbsum/3gi5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3gi5 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
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Check<jmol> | Check<jmol> | ||
<jmolCheckbox> | <jmolCheckbox> | ||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gi/3gi5_consurf.spt"</scriptWhenChecked> | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gi/3gi5_consurf.spt"</scriptWhenChecked> | ||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | ||
<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Nalam, M N.L]] | [[Category: Nalam, M N.L]] | ||
[[Category: Schiffer, C A]] | [[Category: Schiffer, C A]] | ||
Revision as of 23:06, 20 October 2021
Crystal structure of protease inhibitor, KB62 in complex with wild type HIV-1 proteaseCrystal structure of protease inhibitor, KB62 in complex with wild type HIV-1 protease
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedDrug resistance mutations in HIV-1 protease selectively alter inhibitor binding without significantly affecting substrate recognition and cleavage. This alteration in molecular recognition led us to develop the substrate-envelope hypothesis which predicts that HIV-1 protease inhibitors that fit within the overlapping consensus volume of the substrates are less likely to be susceptible to drug-resistant mutations, as a mutation impacting such inhibitors would simultaneously impact the processing of substrates. To evaluate this hypothesis, over 130 HIV-1 protease inhibitors were designed and synthesized using three different approaches with and without substrate-envelope constraints. A subset of 16 representative inhibitors with binding affinities to wild-type protease ranging from 58 nM to 0.8 pM was chosen for crystallographic analysis. The inhibitor-protease complexes revealed that tightly binding inhibitors (at the picomolar level of affinity) appear to "lock" into the protease active site by forming hydrogen bonds to particular active-site residues. Both this hydrogen bonding pattern and subtle variations in protein-ligand van der Waals interactions distinguish nanomolar from picomolar inhibitors. In general, inhibitors that fit within the substrate envelope, regardless of whether they are picomolar or nanomolar, have flatter profiles with respect to drug-resistant protease variants than inhibitors that protrude beyond the substrate envelope; this provides a strong rationale for incorporating substrate-envelope constraints into structure-based design strategies to develop new HIV-1 protease inhibitors. Evaluating the substrate-envelope hypothesis: structural analysis of novel HIV-1 protease inhibitors designed to be robust against drug resistance.,Nalam MN, Ali A, Altman MD, Reddy GS, Chellappan S, Kairys V, Ozen A, Cao H, Gilson MK, Tidor B, Rana TM, Schiffer CA J Virol. 2010 May;84(10):5368-78. Epub 2010 Mar 17. PMID:20237088[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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