1hsg: Difference between revisions

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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

OverviewOverview

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.

About this StructureAbout this Structure

1HSG is a Single protein structure of sequence from Human immunodeficiency virus 1 with as ligand. The following page contains interesting information on the relation of 1HSG with [HIV-1 Protease]. Full crystallographic information is available from OCA.

ReferenceReference

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

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-[[Image:1hsg.gif|left|200px]]<br />
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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'''<br />
 ==Overview==
-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.
+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.
 ==About this Structure==
-HSG 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 MK1 as [http://en.wikipedia.org/wiki/ligand ligand]. The following page contains interesting information on the relation of 1HSG with [[http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb6_1.html HIV-1 Protease]]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1HSG OCA].
+HSG 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=MK1:'>MK1</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. The following page contains interesting information on the relation of 1HSG with [[http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb6_1.html HIV-1 Protease]]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HSG OCA].
 ==Reference==
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 [[Category: hydrolase (acid proteinase)]]
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