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==CRYSTAL STRUCTURE AT 1.9 ANGSTROMS RESOLUTION OF HUMAN IMMUNODEFICIENCY VIRUS (HIV) II PROTEASE COMPLEXED WITH L-735,524, AN ORALLY BIOAVAILABLE INHIBITOR OF THE HIV PROTEASES== | |||
<StructureSection load='1hsg' size='340' side='right' caption='[[1hsg]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[1hsg]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. The June 2000 RCSB PDB [http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''HIV-1 Protease'' by David S. Goodsell is [http://dx.doi.org/10.2210/rcsb_pdb/mom_2000_6 10.2210/rcsb_pdb/mom_2000_6]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HSG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1HSG FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MK1:N-[2(R)-HYDROXY-1(S)-INDANYL]-5-[(2(S)-TERTIARY+BUTYLAMINOCARBONYL)-4(3-PYRIDYLMETHYL)PIPERAZINO]-4(S)-HYDROXY-2(R)-PHENYLMETHYLPENTANAMIDE'>MK1</scene><br> | |||
<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HIV-1 PROTEASE FROM THE NY5 ISOLATE ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 Human immunodeficiency virus 1])</td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1hsg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1hsg OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1hsg RCSB], [http://www.ebi.ac.uk/pdbsum/1hsg PDBsum]</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/hs/1hsg_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/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
L-735,524 is a potent, orally bioavailable inhibitor of human immunodeficiency virus (HIV) protease currently in a Phase II clinical trial. We report here the three-dimensional structure of L-735,524 complexed to HIV-2 protease at 1.9-A resolution, as well as the structure of the native HIV-2 protease at 2.5-A resolution. The structure of HIV-2 protease is found to be essentially identical to that of HIV-1 protease. In the crystal lattice of the HIV-2 protease complexed with L-735,524, the inhibitor is chelated to the active site of the homodimeric enzyme in one orientation. This feature allows an unambiguous assignment of protein-ligand interactions from the electron density map. Both Fourier and difference Fourier maps reveal clearly the closure of the flap domains of the protease upon L-735,524 binding. Specific interactions between the enzyme and the inhibitor include the hydroxy group of the hydroxyaminopentane amide moiety of L-735,524 ligating to the carboxyl groups of the essential Asp-25 and Asp-25' enzymic residues and the amide oxygens of the inhibitor hydrogen bonding to the backbone amide nitrogen of Ile-50 and Ile-50' via an intervening water molecule. A second bridging water molecule is found between the amide nitrogen N2 of L-735,524 and the carboxyl oxygen of Asp-29'. Although other hydrogen bonds also add to binding, an equally significant contribution to affinity arises from hydrophobic interactions between the protease and the inhibitor throughout the pseudo-symmetric S1/S1', S2/S2', and S3/S3' regions of the enzyme. Except for its pyridine ring, all lipophilic moieties (t-butyl, indanyl, benzyl, and piperidyl) of L-735,524 are rigidly defined in the active site. | |||
Crystal structure at 1.9-A resolution of human immunodeficiency virus (HIV) II protease complexed with L-735,524, an orally bioavailable inhibitor of the HIV proteases.,Chen Z, Li Y, Chen E, Hall DL, Darke PL, Culberson C, Shafer JA, Kuo LC J Biol Chem. 1994 Oct 21;269(42):26344-8. PMID:7929352<ref>PMID:7929352</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Indinavir|Indinavir]] | *[[Indinavir|Indinavir]] | ||
*[[Virus protease|Virus protease]] | *[[Virus protease|Virus protease]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: HIV-1 Protease]] | [[Category: HIV-1 Protease]] | ||
[[Category: Human immunodeficiency virus 1]] | [[Category: Human immunodeficiency virus 1]] | ||
[[Category: RCSB PDB Molecule of the Month]] | [[Category: RCSB PDB Molecule of the Month]] | ||
[[Category: Chen, Z.]] | [[Category: Chen, Z.]] | ||
Revision as of 19:18, 29 September 2014
CRYSTAL STRUCTURE AT 1.9 ANGSTROMS RESOLUTION OF HUMAN IMMUNODEFICIENCY VIRUS (HIV) II PROTEASE COMPLEXED WITH L-735,524, AN ORALLY BIOAVAILABLE INHIBITOR OF THE HIV PROTEASESCRYSTAL STRUCTURE AT 1.9 ANGSTROMS RESOLUTION OF HUMAN IMMUNODEFICIENCY VIRUS (HIV) II PROTEASE COMPLEXED WITH L-735,524, AN ORALLY BIOAVAILABLE INHIBITOR OF THE HIV PROTEASES
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedL-735,524 is a potent, orally bioavailable inhibitor of human immunodeficiency virus (HIV) protease currently in a Phase II clinical trial. We report here the three-dimensional structure of L-735,524 complexed to HIV-2 protease at 1.9-A resolution, as well as the structure of the native HIV-2 protease at 2.5-A resolution. The structure of HIV-2 protease is found to be essentially identical to that of HIV-1 protease. In the crystal lattice of the HIV-2 protease complexed with L-735,524, the inhibitor is chelated to the active site of the homodimeric enzyme in one orientation. This feature allows an unambiguous assignment of protein-ligand interactions from the electron density map. Both Fourier and difference Fourier maps reveal clearly the closure of the flap domains of the protease upon L-735,524 binding. Specific interactions between the enzyme and the inhibitor include the hydroxy group of the hydroxyaminopentane amide moiety of L-735,524 ligating to the carboxyl groups of the essential Asp-25 and Asp-25' enzymic residues and the amide oxygens of the inhibitor hydrogen bonding to the backbone amide nitrogen of Ile-50 and Ile-50' via an intervening water molecule. A second bridging water molecule is found between the amide nitrogen N2 of L-735,524 and the carboxyl oxygen of Asp-29'. Although other hydrogen bonds also add to binding, an equally significant contribution to affinity arises from hydrophobic interactions between the protease and the inhibitor throughout the pseudo-symmetric S1/S1', S2/S2', and S3/S3' regions of the enzyme. Except for its pyridine ring, all lipophilic moieties (t-butyl, indanyl, benzyl, and piperidyl) of L-735,524 are rigidly defined in the active site. Crystal structure at 1.9-A resolution of human immunodeficiency virus (HIV) II protease complexed with L-735,524, an orally bioavailable inhibitor of the HIV proteases.,Chen Z, Li Y, Chen E, Hall DL, Darke PL, Culberson C, Shafer JA, Kuo LC J Biol Chem. 1994 Oct 21;269(42):26344-8. PMID:7929352[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences |
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