1hyz
From Proteopedia
(New page: 200px<br /> <applet load="1hyz" size="450" color="white" frame="true" align="right" spinBox="true" caption="1hyz, resolution 2.3Å" /> '''HIV INTEGRASE CORE D...) |
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| - | [[Image:1hyz.gif|left|200px]]<br /> | + | [[Image:1hyz.gif|left|200px]]<br /><applet load="1hyz" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1hyz" size=" | + | |
caption="1hyz, resolution 2.3Å" /> | caption="1hyz, resolution 2.3Å" /> | ||
'''HIV INTEGRASE CORE DOMAIN COMPLEXED WITH A DERIVATIVE OF TETRAPHENYL ARSONIUM.'''<br /> | '''HIV INTEGRASE CORE DOMAIN COMPLEXED WITH A DERIVATIVE OF TETRAPHENYL ARSONIUM.'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Integration of the reverse-transcribed HIV cDNA into the host DNA is a | + | Integration of the reverse-transcribed HIV cDNA into the host DNA is a required step in viral replication. The virus-encoded integrase protein catalyzes the initial DNA breaking and joining reactions that mediate cDNA integration. Here, the identification by X-ray crystallography of a small-molecule binding site on the integrase catalytic domain is reported. The small-molecule family studied consists of a core of arsenic or phosphorus surrounded by four aromatic groups. Two arsenic derivatives were visualized bound to integrase. In each case, two molecules bound at symmetry-related sites on the catalytic domain dimer interface. The first compound studied, tetraphenyl arsonium, did not inhibit integrase. However, a synthetic compound substituting a catechol for one of the phenyl rings, dihydroxyphenyltriphenylarsonium, bound to the same site and did inhibit the enzyme. Changes in the vicinity of the catalytic site were seen with the inhibitory compound only, potentially explaining its mechanism of action. Further substituting phosphonium for arsonium yielded a compound with an IC(50) in the low micromolar range. These findings may be useful in designing new inhibitors of integrase, which is at present the only one of the three HIV enzymes for which clinically useful inhibitors are not available. |
==About this Structure== | ==About this Structure== | ||
| - | 1HYZ 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 SO4, CL and TTO as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/RNA-directed_DNA_polymerase RNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.49 2.7.7.49] Full crystallographic information is available from [http:// | + | 1HYZ 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=SO4:'>SO4</scene>, <scene name='pdbligand=CL:'>CL</scene> and <scene name='pdbligand=TTO:'>TTO</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/RNA-directed_DNA_polymerase RNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.49 2.7.7.49] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HYZ OCA]. |
==Reference== | ==Reference== | ||
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[[Category: RNA-directed DNA polymerase]] | [[Category: RNA-directed DNA polymerase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Bushman, F | + | [[Category: Bushman, F D.]] |
[[Category: Choe, S.]] | [[Category: Choe, S.]] | ||
[[Category: Greenwald, J.]] | [[Category: Greenwald, J.]] | ||
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[[Category: Molteni, V.]] | [[Category: Molteni, V.]] | ||
[[Category: Rhodes, D.]] | [[Category: Rhodes, D.]] | ||
| - | [[Category: Siegel, J | + | [[Category: Siegel, J S.]] |
[[Category: CL]] | [[Category: CL]] | ||
[[Category: SO4]] | [[Category: SO4]] | ||
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[[Category: dna integration]] | [[Category: dna integration]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:06:13 2008'' |
Revision as of 11:06, 21 February 2008
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HIV INTEGRASE CORE DOMAIN COMPLEXED WITH A DERIVATIVE OF TETRAPHENYL ARSONIUM.
Overview
Integration of the reverse-transcribed HIV cDNA into the host DNA is a required step in viral replication. The virus-encoded integrase protein catalyzes the initial DNA breaking and joining reactions that mediate cDNA integration. Here, the identification by X-ray crystallography of a small-molecule binding site on the integrase catalytic domain is reported. The small-molecule family studied consists of a core of arsenic or phosphorus surrounded by four aromatic groups. Two arsenic derivatives were visualized bound to integrase. In each case, two molecules bound at symmetry-related sites on the catalytic domain dimer interface. The first compound studied, tetraphenyl arsonium, did not inhibit integrase. However, a synthetic compound substituting a catechol for one of the phenyl rings, dihydroxyphenyltriphenylarsonium, bound to the same site and did inhibit the enzyme. Changes in the vicinity of the catalytic site were seen with the inhibitory compound only, potentially explaining its mechanism of action. Further substituting phosphonium for arsonium yielded a compound with an IC(50) in the low micromolar range. These findings may be useful in designing new inhibitors of integrase, which is at present the only one of the three HIV enzymes for which clinically useful inhibitors are not available.
About this Structure
1HYZ is a Single protein structure of sequence from Human immunodeficiency virus 1 with , and as ligands. Active as RNA-directed DNA polymerase, with EC number 2.7.7.49 Full crystallographic information is available from OCA.
Reference
Identification of a small-molecule binding site at the dimer interface of the HIV integrase catalytic domain., Molteni V, Greenwald J, Rhodes D, Hwang Y, Kwiatkowski W, Bushman FD, Siegel JS, Choe S, Acta Crystallogr D Biol Crystallogr. 2001 Apr;57(Pt 4):536-44. PMID:11264582
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