2i4d: Difference between revisions

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[[Image:2i4d.jpg|left|200px]]<br /><applet load="2i4d" size="350" color="white" frame="true" align="right" spinBox="true"
caption="2i4d, resolution 1.50&Aring;" />
'''Crystal structure of WT HIV-1 protease with GS-8373'''<br />


==Overview==
==Crystal structure of WT HIV-1 protease with GS-8373==
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.
<StructureSection load='2i4d' size='340' side='right'caption='[[2i4d]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
 
== Structural highlights ==
==About this Structure==
<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>
2I4D 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 <scene name='pdbligand=QFI:'>QFI</scene> 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://oca.weizmann.ac.il/oca-bin/ocashort?id=2I4D OCA].
</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>
 
<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>
==Reference==
<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>
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://ispc.weizmann.ac.il//pmbin/getpm?pmid=16979654 16979654]
</table>
[[Category: HIV-1 retropepsin]]
== Function ==
[https://www.uniprot.org/uniprot/Q5RZ08_9HIV1 Q5RZ08_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/i4/2i4d_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=2i4d ConSurf].
<div style="clear:both"></div>
__TOC__
</StructureSection>
[[Category: Human immunodeficiency virus 1]]
[[Category: Human immunodeficiency virus 1]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Hatada, M.]]
[[Category: Hatada M]]
[[Category: QFI]]
[[Category: hiv-1 protease]]
[[Category: hydrolase]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:49:02 2008''

Latest revision as of 12:01, 21 February 2024

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

Structural highlights

2i4d is a 2 chain structure with sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.5Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

Q5RZ08_9HIV1

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

2i4d, resolution 1.50Å

Drag the structure with the mouse to rotate

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OCA