4npt: Difference between revisions
New page: '''Unreleased structure''' The entry 4npt is ON HOLD Authors: Zhang, Y., Weber, I.T. Description: Crystal Structure of HIV-1 Protease Multiple Mutant P51 Complexed with Darunavir |
No edit summary |
||
| (7 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
The | ==Crystal Structure of HIV-1 Protease Multiple Mutant P51 Complexed with Darunavir== | ||
<StructureSection load='4npt' size='340' side='right'caption='[[4npt]], [[Resolution|resolution]] 1.66Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4npt]] is a 1 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=4NPT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NPT FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.66Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=017:(3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL(1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE'>017</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></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=4npt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4npt OCA], [https://pdbe.org/4npt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4npt RCSB], [https://www.ebi.ac.uk/pdbsum/4npt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4npt ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/O38896_9HIV1 O38896_9HIV1] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The molecular basis for high resistance to clinical inhibitors of HIV-1 protease (PR) was examined for the variant designated PRP51 that was selected for resistance to darunavir (DRV). High resolution crystal structures of PRP51 with the active site D25N mutation revealed a ligand-free form and an inhibitor-bound form showing a unique binding site and orientation for DRV. This inactivating mutation is known to increase the dimer dissociation constant and decrease DRV affinity of PR. The PRP51-D25N dimers were in the open conformation with widely separated flaps, as reported for other highly resistant variants. PRP51-D25N dimer bound two DRV molecules and showed larger separation of 8.7 A between the closest atoms of the two flaps compared with 4.4 A for the ligand-free structure of this mutant. The ligand-free structure, however, lacked van der Waals contacts between Ile50 and Pro81' from the other subunit in the dimer, unlike the majority of PR structures. DRV is bound inside the active site cavity; however, the inhibitor is oriented almost perpendicular to its typical position and exhibits only 2 direct hydrogen bond and two water-mediated interactions with atoms of PRP51-D25N compared with 11 hydrogen bond interactions seen for DRV bound in the typical position in wild-type enzyme. The atypical location of DRV may provide opportunities for design of novel inhibitors targeting the open conformation of PR drug-resistant mutants. | |||
Structures of darunavir-resistant HIV-1 protease mutant reveal atypical binding of darunavir to wide open flaps.,Zhang Y, Chang YC, Louis JM, Wang YF, Harrison RW, Weber IT ACS Chem Biol. 2014 Jun 20;9(6):1351-8. doi: 10.1021/cb4008875. Epub 2014 Apr 28. PMID:24738918<ref>PMID:24738918</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4npt" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Immunodeficiency virus protease 3D structures|Immunodeficiency virus protease 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Human immunodeficiency virus 1]] | |||
[[Category: Large Structures]] | |||
[[Category: Weber IT]] | |||
[[Category: Zhang Y]] | |||
Latest revision as of 20:01, 20 September 2023
Structural highlights
FunctionPublication Abstract from PubMedThe molecular basis for high resistance to clinical inhibitors of HIV-1 protease (PR) was examined for the variant designated PRP51 that was selected for resistance to darunavir (DRV). High resolution crystal structures of PRP51 with the active site D25N mutation revealed a ligand-free form and an inhibitor-bound form showing a unique binding site and orientation for DRV. This inactivating mutation is known to increase the dimer dissociation constant and decrease DRV affinity of PR. The PRP51-D25N dimers were in the open conformation with widely separated flaps, as reported for other highly resistant variants. PRP51-D25N dimer bound two DRV molecules and showed larger separation of 8.7 A between the closest atoms of the two flaps compared with 4.4 A for the ligand-free structure of this mutant. The ligand-free structure, however, lacked van der Waals contacts between Ile50 and Pro81' from the other subunit in the dimer, unlike the majority of PR structures. DRV is bound inside the active site cavity; however, the inhibitor is oriented almost perpendicular to its typical position and exhibits only 2 direct hydrogen bond and two water-mediated interactions with atoms of PRP51-D25N compared with 11 hydrogen bond interactions seen for DRV bound in the typical position in wild-type enzyme. The atypical location of DRV may provide opportunities for design of novel inhibitors targeting the open conformation of PR drug-resistant mutants. Structures of darunavir-resistant HIV-1 protease mutant reveal atypical binding of darunavir to wide open flaps.,Zhang Y, Chang YC, Louis JM, Wang YF, Harrison RW, Weber IT ACS Chem Biol. 2014 Jun 20;9(6):1351-8. doi: 10.1021/cb4008875. Epub 2014 Apr 28. PMID:24738918[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||