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==Joint X-ray/neutron structure of HIV-1 protease triple mutant (V32I,I47V,V82I) with tetrahedral intermediate mimic KVS-1== | ==Joint X-ray/neutron structure of HIV-1 protease triple mutant (V32I,I47V,V82I) with tetrahedral intermediate mimic KVS-1== | ||
<StructureSection load='6ptp' size='340' side='right'caption='[[6ptp]]' scene=''> | <StructureSection load='6ptp' size='340' side='right'caption='[[6ptp]], [[Resolution|resolution]] 1.85Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PTP OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6PTP FirstGlance]. <br> | <table><tr><td colspan='2'>[[6ptp]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/9hiv1 9hiv1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PTP OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6PTP FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6ptp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ptp OCA], [http://pdbe.org/6ptp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ptp RCSB], [http://www.ebi.ac.uk/pdbsum/6ptp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ptp ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DOD:DEUTERATED+WATER'>DOD</scene>, <scene name='pdbligand=KVS:N~2~-[(2R,5S)-5-({(2S,3S)-2-[(N-ACETYL-L-THREONYL)AMINO]-3-METHYLPENT-4-ENOYL}AMINO)-2-BUTYL-4,4-DIHYDROXYNONANOYL]-L-GLUTAMINYL-L-ARGININAMIDE'>KVS</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">pol ([http://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'>[http://proteopedia.org/fgij/fg.htm?mol=6ptp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ptp OCA], [http://pdbe.org/6ptp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ptp RCSB], [http://www.ebi.ac.uk/pdbsum/6ptp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ptp ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
HIV-1 protease is indispensable for virus propagation and an important therapeutic target for antiviral inhibitors to treat AIDS. As such inhibitors are transition-state mimics, a detailed understanding of the enzyme mechanism is crucial for the development of better anti-HIV drugs. Here, we used room-temperature joint X-ray/neutron crystallography to directly visualize hydrogen atoms and map hydrogen bonding interactions in a protease complex with peptidomimetic inhibitor KVS-1 containing a reactive nonhydrolyzable ketomethylene isostere, which, upon reacting with the catalytic water molecule, is converted into a tetrahedral intermediate state, KVS-1TI. We unambiguously determined that the resulting tetrahedral intermediate is an oxyanion, rather than the gem-diol, and both catalytic aspartic acid residues are protonated. The oxyanion tetrahedral intermediate appears to be unstable, even though the negative charge on the oxyanion is delocalized through a strong n --> pi* hyperconjugative interaction into the nearby peptidic carbonyl group of the inhibitor. To better understand the influence of the ketomethylene isostere as a protease inhibitor, we have also examined the protease structure and binding affinity with keto-darunavir (keto-DRV), which similar to KVS-1 includes the ketomethylene isostere. We show that keto-DRV is a significantly less potent protease inhibitor than DRV. These findings shed light on the reaction mechanism of peptide hydrolysis catalyzed by HIV-1 protease and provide valuable insights into further improvements in the design of protease inhibitors. | |||
Visualizing Tetrahedral Oxyanion Bound in HIV-1 Protease Using Neutrons: Implications for the Catalytic Mechanism and Drug Design.,Kumar M, Mandal K, Blakeley MP, Wymore T, Kent SBH, Louis JM, Das A, Kovalevsky A ACS Omega. 2020 May 14;5(20):11605-11617. doi: 10.1021/acsomega.0c00835., eCollection 2020 May 26. PMID:32478251<ref>PMID:32478251</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6ptp" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Das A]] | [[Category: Das, A]] | ||
[[Category: Kovalevsky A]] | [[Category: Kovalevsky, A]] | ||
[[Category: Aspartic protease]] | |||
[[Category: Hiv-1 protease]] | |||
[[Category: Homodimer]] | |||
[[Category: Hydrolase]] | |||