View source for 1rpi


==Crystal structures of a Multidrug-Resistant HIV-1 Protease Reveal an Expanded Active Site Cavity==
<StructureSection load='1rpi' size='340' side='right'caption='[[1rpi]], [[Resolution|resolution]] 1.86&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1rpi]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/9hiv1 9hiv1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RPI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1RPI FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1rq9|1rq9]], [[1rv7|1rv7]]</div></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HIV-1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 9HIV1])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/HIV-1_retropepsin HIV-1 retropepsin], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.16 3.4.23.16] </span></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=1rpi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1rpi OCA], [https://pdbe.org/1rpi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1rpi RCSB], [https://www.ebi.ac.uk/pdbsum/1rpi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1rpi ProSAT]</span></td></tr>
</table>
== 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/rp/1rpi_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=1rpi ConSurf].
<div style="clear:both"></div>
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== Publication Abstract from PubMed ==
The goal of this study was to use X-ray crystallography to investigate the structural basis of resistance to human immunodeficiency virus type 1 (HIV-1) protease inhibitors. We overexpressed, purified, and crystallized a multidrug-resistant (MDR) HIV-1 protease enzyme derived from a patient failing on several protease inhibitor-containing regimens. This HIV-1 variant contained codon mutations at positions 10, 36, 46, 54, 63, 71, 82, 84, and 90 that confer drug resistance to protease inhibitors. The 1.8-angstrom (A) crystal structure of this MDR patient isolate reveals an expanded active-site cavity. The active-site expansion includes position 82 and 84 mutations due to the alterations in the amino acid side chains from longer to shorter (e.g., V82A and I84V). The MDR isolate 769 protease "flaps" stay open wider, and the difference in the flap tip distances in the MDR 769 variant is 12 A. The MDR 769 protease crystal complexes with lopinavir and DMP450 reveal completely different binding modes. The network of interactions between the ligands and the MDR 769 protease is completely different from that seen with the wild-type protease-ligand complexes. The water molecule-forming hydrogen bonds bridging between the two flaps and either the substrate or the peptide-based inhibitor are lacking in the MDR 769 clinical isolate. The S1, S1', S3, and S3' pockets show expansion and conformational change. Surface plasmon resonance measurements with the MDR 769 protease indicate higher k(off) rates, resulting in a change of binding affinity. Surface plasmon resonance measurements provide k(on) and k(off) data (K(d) = k(off)/k(on)) to measure binding of the multidrug-resistant protease to various ligands. This MDR 769 protease represents a new antiviral target, presenting the possibility of designing novel inhibitors with activity against the open and expanded protease forms.

Crystal structures of a multidrug-resistant human immunodeficiency virus type 1 protease reveal an expanded active-site cavity.,Logsdon BC, Vickrey JF, Martin P, Proteasa G, Koepke JI, Terlecky SR, Wawrzak Z, Winters MA, Merigan TC, Kovari LC J Virol. 2004 Mar;78(6):3123-32. PMID:14990731<ref>PMID:14990731</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 1rpi" style="background-color:#fffaf0;"></div>

==See Also==
*[[Immunodeficiency virus protease 3D structures|Immunodeficiency virus protease 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: HIV-1 retropepsin]]
[[Category: Large Structures]]
[[Category: Koepke, J I]]
[[Category: Kovari, L C]]
[[Category: Logsdon, B C]]
[[Category: Martin, P]]
[[Category: Merigan, T C]]
[[Category: Proteasa, G]]
[[Category: Terlecky, S R]]
[[Category: Vickrey, J F]]
[[Category: Wawrzak, Z]]
[[Category: Winters, M A]]
[[Category: Aid]]
[[Category: Aspartyl portease]]
[[Category: Hiv protease]]
[[Category: Hydrolase]]
[[Category: Multi-drug resistance]]
[[Category: Polyprotein]]