1rpi

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(New page: 200px<br /> <applet load="1rpi" size="450" color="white" frame="true" align="right" spinBox="true" caption="1rpi, resolution 1.86&Aring;" /> '''Crystal structures ...)
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[[Image:1rpi.gif|left|200px]]<br />
 
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<applet load="1rpi" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1rpi, resolution 1.86&Aring;" />
 
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'''Crystal structures of a Multidrug-Resistant HIV-1 Protease Reveal an Expanded Active Site Cavity'''<br />
 
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==Overview==
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==Crystal structures of a Multidrug-Resistant HIV-1 Protease Reveal an Expanded Active Site Cavity==
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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.
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<StructureSection load='1rpi' size='340' side='right'caption='[[1rpi]], [[Resolution|resolution]] 1.86&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1rpi]] 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=1RPI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1RPI FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.86&#8491;</td></tr>
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<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>
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<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>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/Q9QM22_9HIV1 Q9QM22_9HIV1]
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/rp/1rpi_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1RPI is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] with GLC as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/HIV-1_retropepsin HIV-1 retropepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.16 3.4.23.16] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1RPI OCA].
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*[[Immunodeficiency virus protease 3D structures|Immunodeficiency virus protease 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=14990731 14990731]
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[[Category: HIV-1 retropepsin]]
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[[Category: Human immunodeficiency virus 1]]
[[Category: Human immunodeficiency virus 1]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Koepke, J.I.]]
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[[Category: Koepke JI]]
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[[Category: Kovari, L.C.]]
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[[Category: Kovari LC]]
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[[Category: Logsdon, B.C.]]
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[[Category: Logsdon BC]]
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[[Category: Martin, P.]]
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[[Category: Martin P]]
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[[Category: Merigan, T.C.]]
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[[Category: Merigan TC]]
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[[Category: Proteasa, G.]]
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[[Category: Proteasa G]]
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[[Category: Terlecky, S.R.]]
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[[Category: Terlecky SR]]
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[[Category: Vickrey, J.F.]]
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[[Category: Vickrey JF]]
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[[Category: Wawrzak, Z.]]
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[[Category: Wawrzak Z]]
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[[Category: Winters, M.A.]]
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[[Category: Winters MA]]
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[[Category: GLC]]
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[[Category: aids]]
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[[Category: aspartyl portease]]
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[[Category: hiv protease]]
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[[Category: hydrolase]]
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[[Category: multi-drug resistance]]
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[[Category: polyprotein]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Thu Nov 8 14:25:46 2007''
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Current revision

Crystal structures of a Multidrug-Resistant HIV-1 Protease Reveal an Expanded Active Site Cavity

PDB ID 1rpi

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