1b11: Difference between revisions

Revision as of 12:50, 21 February 2008

STRUCTURE OF FELINE IMMUNODEFICIENCY VIRUS PROTEASE COMPLEXED WITH TL-3-093

OverviewOverview

Three forms of feline immunodeficiency virus protease (FIV PR), the wild type (wt) and two single point mutants, V59I and Q99V, as well as human immunodeficiency virus type 1 protease (HIV-1 PR), were cocrystallized with the C2-symmetric inhibitor, TL-3. The mutants of FIV PR were designed to replace residues involved in enzyme-ligand interactions by the corresponding HIV-1 PR residues at the structurally equivalent position. TL-3 shows decreased (improved) inhibition constants with these FIV PR mutants relative to wt FIV PR. Despite similar modes of binding of the inhibitor to all PRs (from P3 to P3'), small differences are evident in the conformation of the Phe side chains of TL-3 at the P1 and P1' positions in the complexes with the mutated FIV PRs. The differences mimick the observed binding of TL-3 in HIV-1 PR and correlate with a significant improvement in the inhibition constants of TL-3 with the two mutant FIV PRs. Large differences between the HIV-1 and FIV PR complexes are evident in the binding modes of the carboxybenzyl groups of TL-3 at P4 and P4'. In HIV-1 PR:TL-3, these groups bind over the flap region, whereas in the FIV PR complexes, the rings are located along the major axis of the active site. A significant difference in the location of the flaps in this region of the HIV-1 and FIV PRs correlates with the observed conformational changes in the binding mode of the peptidomimetic inhibitor at the P4 and P4' positions. These findings provide a structural explanation of the observed Ki values for TL-3 with the different PRs and will further assist in the development of improved inhibitors.

About this StructureAbout this Structure

1B11 is a Single protein structure of sequence from Feline immunodeficiency virus with and as ligands. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.

ReferenceReference

Structural studies of FIV and HIV-1 proteases complexed with an efficient inhibitor of FIV protease., Li M, Morris GM, Lee T, Laco GS, Wong CH, Olson AJ, Elder JH, Wlodawer A, Gustchina A, Proteins. 2000 Jan 1;38(1):29-40. PMID:10651036

Page seeded by OCA on Thu Feb 21 11:50:23 2008

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OCA

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-[[Image:1b11.gif|left|200px]]<br />
+[[Image:1b11.gif|left|200px]]<br /><applet load="1b11" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1b11" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1b11, resolution 1.9&Aring;" />
 '''STRUCTURE OF FELINE IMMUNODEFICIENCY VIRUS PROTEASE COMPLEXED WITH TL-3-093'''<br />
 ==Overview==
-Three forms of feline immunodeficiency virus protease (FIV PR), the wild, type (wt) and two single point mutants, V59I and Q99V, as well as human, immunodeficiency virus type 1 protease (HIV-1 PR), were cocrystallized, with the C2-symmetric inhibitor, TL-3. The mutants of FIV PR were designed, to replace residues involved in enzyme-ligand interactions by the, corresponding HIV-1 PR residues at the structurally equivalent position., TL-3 shows decreased (improved) inhibition constants with these FIV PR, mutants relative to wt FIV PR. Despite similar modes of binding of the, inhibitor to all PRs (from P3 to P3'), small differences are evident in, the conformation of the Phe side chains of TL-3 at the P1 and P1', positions in the complexes with the mutated FIV PRs. The differences, mimick the observed binding of TL-3 in HIV-1 PR and correlate with a, significant improvement in the inhibition constants of TL-3 with the two, mutant FIV PRs. Large differences between the HIV-1 and FIV PR complexes, are evident in the binding modes of the carboxybenzyl groups of TL-3 at P4, and P4'. In HIV-1 PR:TL-3, these groups bind over the flap region, whereas, in the FIV PR complexes, the rings are located along the major axis of the, active site. A significant difference in the location of the flaps in this, region of the HIV-1 and FIV PRs correlates with the observed, conformational changes in the binding mode of the peptidomimetic inhibitor, at the P4 and P4' positions. These findings provide a structural, explanation of the observed Ki values for TL-3 with the different PRs and, will further assist in the development of improved inhibitors.
+Three forms of feline immunodeficiency virus protease (FIV PR), the wild type (wt) and two single point mutants, V59I and Q99V, as well as human immunodeficiency virus type 1 protease (HIV-1 PR), were cocrystallized with the C2-symmetric inhibitor, TL-3. The mutants of FIV PR were designed to replace residues involved in enzyme-ligand interactions by the corresponding HIV-1 PR residues at the structurally equivalent position. TL-3 shows decreased (improved) inhibition constants with these FIV PR mutants relative to wt FIV PR. Despite similar modes of binding of the inhibitor to all PRs (from P3 to P3'), small differences are evident in the conformation of the Phe side chains of TL-3 at the P1 and P1' positions in the complexes with the mutated FIV PRs. The differences mimick the observed binding of TL-3 in HIV-1 PR and correlate with a significant improvement in the inhibition constants of TL-3 with the two mutant FIV PRs. Large differences between the HIV-1 and FIV PR complexes are evident in the binding modes of the carboxybenzyl groups of TL-3 at P4 and P4'. In HIV-1 PR:TL-3, these groups bind over the flap region, whereas in the FIV PR complexes, the rings are located along the major axis of the active site. A significant difference in the location of the flaps in this region of the HIV-1 and FIV PRs correlates with the observed conformational changes in the binding mode of the peptidomimetic inhibitor at the P4 and P4' positions. These findings provide a structural explanation of the observed Ki values for TL-3 with the different PRs and will further assist in the development of improved inhibitors.
 ==About this Structure==
-B11 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Feline_immunodeficiency_virus Feline immunodeficiency virus] with SO4 and INT as [http://en.wikipedia.org/wiki/ligands ligands]. 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=1B11 OCA].
+B11 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Feline_immunodeficiency_virus Feline immunodeficiency virus] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=INT:'>INT</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. 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=1B11 OCA].
 ==Reference==
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 [[Category: inhibitor]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Thu Nov  8 13:52:17 2007''
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