View source for 4tvh


==HIV Protease (PR) dimer in closed form with TL-3 in active site and fragment AK-2097 in the outside/top of flap==
<StructureSection load='4tvh' size='340' side='right'caption='[[4tvh]], [[Resolution|resolution]] 2.19&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4tvh]] 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=4TVH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TVH 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]] 2.195&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3TL:BENZYL+[(1S,4S,7S,8R,9R,10S,13S,16S)-7,10-DIBENZYL-8,9-DIHYDROXY-1,16-DIMETHYL-4,13-BIS(1-METHYLETHYL)-2,5,12,15,18-PENTAOXO-20-PHENYL-19-OXA-3,6,11,14,17-PENTAAZAICOS-1-YL]CARBAMATE'>3TL</scene>, <scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=K97:3-(MORPHOLIN-4-YLMETHYL)-1H-INDOLE-6-CARBOXYLIC+ACID'>K97</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=4tvh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tvh OCA], [https://pdbe.org/4tvh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4tvh RCSB], [https://www.ebi.ac.uk/pdbsum/4tvh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4tvh ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q90EA1_HV1 Q90EA1_HV1] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Molecular docking is a powerful tool used in drug discovery and structural biology for predicting the structures of ligand-receptor complexes. However, the accuracy of docking calculations can be limited by factors such as the neglect of protein reorganization in the scoring function; as a result, ligand screening can produce a high rate of false positive hits. Although absolute binding free energy methods still have difficulty in accurately rank-ordering binders, we believe that they can be fruitfully employed to distinguish binders from nonbinders and reduce the false positive rate. Here we study a set of ligands that dock favorably to a newly discovered, potentially allosteric site on the flap of HIV-1 protease. Fragment binding to this site stabilizes a closed form of protease, which could be exploited for the design of allosteric inhibitors. Twenty-three top-ranked protein-ligand complexes from AutoDock were subject to the free energy screening using two methods, the recently developed binding energy analysis method (BEDAM) and the standard double decoupling method (DDM). Free energy calculations correctly identified most of the false positives (&gt;/=83%) and recovered all the confirmed binders. The results show a gap averaging &gt;/=3.7 kcal/mol, separating the binders and the false positives. We present a formula that decomposes the binding free energy into contributions from the receptor conformational macrostates, which provides insights into the roles of different binding modes. Our binding free energy component analysis further suggests that improving the treatment for the desolvation penalty associated with the unfulfilled polar groups could reduce the rate of false positive hits in docking. The current study demonstrates that the combination of docking with free energy methods can be very useful for more accurate ligand screening against valuable drug targets.

Distinguishing Binders from False Positives by Free Energy Calculations: Fragment Screening Against the Flap Site of HIV Protease.,Deng N, Forli S, He P, Perryman A, Wickstrom L, Vijayan RS, Tiefenbrunn T, Stout D, Gallicchio E, Olson AJ, Levy RM J Phys Chem B. 2014 Sep 17. PMID:25189630<ref>PMID:25189630</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4tvh" 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: Finn MG]]
[[Category: Kislukhin A]]
[[Category: Stout CD]]
[[Category: Tiefenbrunn T]]