View source for 2pk5


==Crystal Structure of HIV-1 Protease (Q7K, L33I, L63I ) in Complex with KNI-10075==
<StructureSection load='2pk5' size='340' side='right'caption='[[2pk5]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2pk5]] 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=2PK5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2PK5 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]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=075:(4R)-N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-3-[(2S,3S)-2-hydroxy-3-({N-[(isoquinolin-5-yloxy)acetyl]-3-(methyl+sulfonyl)-L-alanyl}amino)-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide'>075</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=2pk5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pk5 OCA], [https://pdbe.org/2pk5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2pk5 RCSB], [https://www.ebi.ac.uk/pdbsum/2pk5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2pk5 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q9J2P7_9HIV1 Q9J2P7_9HIV1] 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/pk/2pk5_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2pk5 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A common strategy to improve the potency of drug candidates is to introduce chemical functionalities, like hydrogen bond donors or acceptors, at positions where they are able to establish strong interactions with the target. However, it is often observed that the added functionalities do not necessarily improve potency even if they form strong hydrogen bonds. Here, we explore the thermodynamic and structural basis for those observations. KNI-10033 is a potent experimental HIV-1 protease inhibitor with picomolar affinity against the wild-type enzyme (K(d) = 13 pm). The potency of the inhibitor is the result of favorable enthalpic (DeltaH = -8.2 kcal/mol) and entropic (-TDeltaS = -6.7 kcal/mol) interactions. The replacement of the thioether group in KNI-10033 by a sulfonyl group (KNI-10075) results in a strong hydrogen bond with the amide of Asp 30B of the HIV-1 protease. This additional hydrogen bond improves the binding enthalpy by 3.9 kcal/mol; however, the enthalpy gain is completely compensated by an entropy loss, resulting in no affinity change. Crystallographic and thermodynamic analysis of the inhibitor/protease complexes indicates that the entropy losses are due to a combination of conformational and solvation effects. These results provide a set of practical guidelines aimed at overcoming enthalpy/entropy compensation and improve binding potency.

Compensating enthalpic and entropic changes hinder binding affinity optimization.,Lafont V, Armstrong AA, Ohtaka H, Kiso Y, Mario Amzel L, Freire E Chem Biol Drug Des. 2007 Jun;69(6):413-22. PMID:17581235<ref>PMID:17581235</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 2pk5" 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: Amzel LM]]
[[Category: Armstrong AA]]
[[Category: Freire E]]
[[Category: Kiso Y]]
[[Category: Lafont V]]