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2i4d

From Proteopedia

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[[Image:2i4d.jpg|left|200px]]
 
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{{Structure
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==Crystal structure of WT HIV-1 protease with GS-8373==
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|PDB= 2i4d |SIZE=350|CAPTION= <scene name='initialview01'>2i4d</scene>, resolution 1.50&Aring;
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<StructureSection load='2i4d' size='340' side='right'caption='[[2i4d]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
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|SITE=
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=QFI:({4-[(2S,3R)-2-({[(3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YLOXY]CARBONYL}AMINO)-3-HYDROXY-4-{ISOBUTYL[(4-METHOXYPHENYL)SULFONYL]AMINO}BUTYL]PHENOXY}METHYL)PHOSPHONIC+ACID'>QFI</scene>
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<table><tr><td colspan='2'>[[2i4d]] 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=2I4D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2I4D FirstGlance]. <br>
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|ACTIVITY= <span class='plainlinks'>[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] </span>
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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]] 1.5&#8491;</td></tr>
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|GENE= gag ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 Human immunodeficiency virus 1])
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QFI:({4-[(2S,3R)-2-({[(3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YLOXY]CARBONYL}AMINO)-3-HYDROXY-4-{ISOBUTYL[(4-METHOXYPHENYL)SULFONYL]AMINO}BUTYL]PHENOXY}METHYL)PHOSPHONIC+ACID'>QFI</scene></td></tr>
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|DOMAIN=
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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=2i4d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2i4d OCA], [https://pdbe.org/2i4d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2i4d RCSB], [https://www.ebi.ac.uk/pdbsum/2i4d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2i4d ProSAT]</span></td></tr>
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|RELATEDENTRY=[[2i4u|2I4U]], [[2i4v|2I4V]], [[2i4w|2I4W]], [[2i4x|2I4X]]
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</table>
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2i4d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2i4d OCA], [http://www.ebi.ac.uk/pdbsum/2i4d PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2i4d RCSB]</span>
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== Function ==
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}}
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[https://www.uniprot.org/uniprot/Q5RZ08_9HIV1 Q5RZ08_9HIV1]
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== Evolutionary Conservation ==
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'''Crystal structure of WT HIV-1 protease with GS-8373'''
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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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==Overview==
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/i4/2i4d_consurf.spt"</scriptWhenChecked>
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The introduction of human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) markedly improved the clinical outcome and control of HIV-1 infection. However, cross-resistance among PIs due to a wide spectrum of mutations in viral protease is a major factor limiting their broader clinical use. Here we report on the suppression of PI resistance using a covalent attachment of a phosphonic acid motif to a peptidomimetic inhibitor scaffold. The resulting phosphonate analogs maintain high binding affinity to HIV-1 protease, potent antiretroviral activity, and unlike the parent molecules, display no loss of potency against a panel of clinically important PI-resistant HIV-1 strains. As shown by crystallographic analysis, the phosphonate moiety is highly exposed to solvent with no discernable interactions with any of the enzyme active site or surface residues. We term this effect "solvent anchoring" and demonstrate that it is driven by a favorable change in the inhibitor binding entropy upon the interaction with mutant enzymes. This type of thermodynamic behavior, which was not found with the parent scaffold fully buried in the enzyme active site, is a result of the increased degeneracy of inhibitor binding states, allowing effective molecular adaptation to the expanded cavity volume of mutant proteases. This strategy, which is applicable to various PI scaffolds, should facilitate the design of novel PIs and potentially other antiviral therapeutics.
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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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==About this Structure==
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</jmolCheckbox>
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2I4D is a [[Single protein]] structure of sequence from [http://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=2I4D OCA].
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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=2i4d ConSurf].
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<div style="clear:both"></div>
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==Reference==
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__TOC__
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Suppression of HIV-1 protease inhibitor resistance by phosphonate-mediated solvent anchoring., Cihlar T, He GX, Liu X, Chen JM, Hatada M, Swaminathan S, McDermott MJ, Yang ZY, Mulato AS, Chen X, Leavitt SA, Stray KM, Lee WA, J Mol Biol. 2006 Oct 27;363(3):635-47. Epub 2006 Aug 2. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16979654 16979654]
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</StructureSection>
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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: Hatada, M.]]
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[[Category: Hatada M]]
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[[Category: hiv-1 protease]]
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[[Category: hydrolase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:39:30 2008''
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Current revision

Crystal structure of WT HIV-1 protease with GS-8373

PDB ID 2i4d

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