3nf7: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Structural basis for a new mechanism of inhibition of HIV integrase identified by fragment screening and structure based design== | ==Structural basis for a new mechanism of inhibition of HIV integrase identified by fragment screening and structure based design== | ||
<StructureSection load='3nf7' size='340' side='right' caption='[[3nf7]], [[Resolution|resolution]] 1.80Å' scene=''> | <StructureSection load='3nf7' size='340' side='right'caption='[[3nf7]], [[Resolution|resolution]] 1.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3nf7]] 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=3NF7 OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[3nf7]] 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=3NF7 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=3NF7 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=CIW:5-[(5-CHLORO-2-OXO-2,3-DIHYDRO-1H-INDOL-1-YL)METHYL]-1,3-BENZODIOXOLE-4-CARBOXYLIC+ACID'>CIW</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=CIW:5-[(5-CHLORO-2-OXO-2,3-DIHYDRO-1H-INDOL-1-YL)METHYL]-1,3-BENZODIOXOLE-4-CARBOXYLIC+ACID'>CIW</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1bhl|1bhl]], [[1bi4|1bi4]], [[1biu|1biu]], [[1ex4|1ex4]], [[1k6y|1k6y]], [[3nf6|3nf6]], [[3nf8|3nf8]], [[3nf9|3nf9]], [[3nfa|3nfa]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1bhl|1bhl]], [[1bi4|1bi4]], [[1biu|1biu]], [[1ex4|1ex4]], [[1k6y|1k6y]], [[3nf6|3nf6]], [[3nf8|3nf8]], [[3nf9|3nf9]], [[3nfa|3nfa]]</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=3nf7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nf7 OCA], [http://pdbe.org/3nf7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3nf7 RCSB], [http://www.ebi.ac.uk/pdbsum/3nf7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3nf7 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
| Line 19: | Line 19: | ||
==See Also== | ==See Also== | ||
*[[Retroviral | *[[Retroviral integrase 3D structures|Retroviral integrase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Deadman, J J]] | [[Category: Deadman, J J]] | ||
[[Category: Newman, J]] | [[Category: Newman, J]] | ||
Revision as of 12:03, 21 October 2020
Structural basis for a new mechanism of inhibition of HIV integrase identified by fragment screening and structure based designStructural basis for a new mechanism of inhibition of HIV integrase identified by fragment screening and structure based design
Structural highlights
Publication Abstract from PubMedBACKGROUND: HIV-1 integrase is a clinically validated therapeutic target for the treatment of HIV-1 infection, with one approved therapeutic currently on the market. This enzyme represents an attractive target for the development of new inhibitors to HIV-1 that are effective against the current resistance mutations. METHODS: A fragment-based screening method employing surface plasmon resonance and NMR was initially used to detect interactions between integrase and fragments. The binding sites of the fragments were elucidated by crystallography and the structural information used to design and synthesize improved ligands. RESULTS: The location of binding of fragments to the catalytic core of integrase was found to be in a previously undescribed binding site, adjacent to the mobile loop. Enzyme assays confirmed that formation of enzyme-fragment complexes inhibits the catalytic activity of integrase and the structural data was utilized to further develop these fragments into more potent novel enzyme inhibitors. CONCLUSIONS: We have defined a new site in integrase as a valid region for the structure-based design of allosteric integrase inhibitors. Using a structure-based design process we have improved the activity of the initial fragments 45-fold. Structural basis for a new mechanism of inhibition of HIV-1 integrase identified by fragment screening and structure-based design.,Rhodes DI, Peat TS, Vandegraaff N, Jeevarajah D, Le G, Jones ED, Smith JA, Coates JA, Winfield LJ, Thienthong N, Newman J, Lucent D, Ryan JH, Savage GP, Francis CL, Deadman JJ Antivir Chem Chemother. 2011 Mar 7;21(4):155-68. PMID:21602613[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||