2ien

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{{STRUCTURE_2ien| PDB=2ien | SCENE= }}
{{STRUCTURE_2ien| PDB=2ien | SCENE= }}
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'''Crystal structure analysis of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017)'''
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===Crystal structure analysis of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017)===
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==Overview==
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The compound UIC-94017 (TMC-114) is a second-generation HIV protease inhibitor with improved pharmacokinetics that is chemically related to the clinical inhibitor amprenavir. UIC-94017 is a broad-spectrum potent inhibitor active against HIV-1 clinical isolates with minimal cytotoxicity. We have determined the high-resolution crystal structures of UIC-94017 in complexes with wild-type HIV-1 protease (PR) and mutant proteases PR(V82A) and PR(I84V) that are common in drug-resistant HIV. The structures were refined at resolutions of 1.10-1.53A. The crystal structures of PR and PR(I84V) with UIC-94017 ternary complexes show that the inhibitor binds to the protease in two overlapping positions, while the PR(V82A) complex had one ordered inhibitor. In all three structures, UIC-94017 forms hydrogen bonds with the conserved main-chain atoms of Asp29 and Asp30 of the protease. These interactions are proposed to be critical for the potency of this compound against HIV isolates that are resistant to multiple protease inhibitors. Other small differences were observed in the interactions of the mutants with UIC-94017 as compared to PR. PR(V82A) showed differences in the position of the main-chain atoms of residue 82 compared to PR structure that better accommodated the inhibitor. Finally, the 1.10A resolution structure of PR(V82A) with UIC-94017 showed an unusual distribution of electron density for the catalytic aspartate residues, which is discussed in relation to the reaction mechanism.
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(as it appears on PubMed at http://www.pubmed.gov), where 15066436 is the PubMed ID number.
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{{ABSTRACT_PUBMED_15066436}}
==About this Structure==
==About this Structure==
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==Reference==
==Reference==
High resolution crystal structures of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017) active against multi-drug-resistant clinical strains., Tie Y, Boross PI, Wang YF, Gaddis L, Hussain AK, Leshchenko S, Ghosh AK, Louis JM, Harrison RW, Weber IT, J Mol Biol. 2004 Apr 23;338(2):341-52. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15066436 15066436]
High resolution crystal structures of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017) active against multi-drug-resistant clinical strains., Tie Y, Boross PI, Wang YF, Gaddis L, Hussain AK, Leshchenko S, Ghosh AK, Louis JM, Harrison RW, Weber IT, J Mol Biol. 2004 Apr 23;338(2):341-52. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15066436 15066436]
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Novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI) UIC-94017 (TMC114) with potent activity against multi-PI-resistant human immunodeficiency virus in vitro., Koh Y, Nakata H, Maeda K, Ogata H, Bilcer G, Devasamudram T, Kincaid JF, Boross P, Wang YF, Tie Y, Volarath P, Gaddis L, Harrison RW, Weber IT, Ghosh AK, Mitsuya H, Antimicrob Agents Chemother. 2003 Oct;47(10):3123-9. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14506019 14506019]
[[Category: HIV-1 retropepsin]]
[[Category: HIV-1 retropepsin]]
[[Category: Human immunodeficiency virus 1]]
[[Category: Human immunodeficiency virus 1]]
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[[Category: Tmc114]]
[[Category: Tmc114]]
[[Category: Uic-94017]]
[[Category: Uic-94017]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 07:24:59 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 08:36:36 2008''

Revision as of 05:36, 28 July 2008

Image:2ien.png

Template:STRUCTURE 2ien

Crystal structure analysis of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017)

Template:ABSTRACT PUBMED 15066436

About this Structure

2IEN is a Single protein structure of sequence from Human immunodeficiency virus 1. This structure supersedes the now removed PDB entry 1s6g. Full crystallographic information is available from OCA.

Reference

High resolution crystal structures of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017) active against multi-drug-resistant clinical strains., Tie Y, Boross PI, Wang YF, Gaddis L, Hussain AK, Leshchenko S, Ghosh AK, Louis JM, Harrison RW, Weber IT, J Mol Biol. 2004 Apr 23;338(2):341-52. PMID:15066436

Novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI) UIC-94017 (TMC114) with potent activity against multi-PI-resistant human immunodeficiency virus in vitro., Koh Y, Nakata H, Maeda K, Ogata H, Bilcer G, Devasamudram T, Kincaid JF, Boross P, Wang YF, Tie Y, Volarath P, Gaddis L, Harrison RW, Weber IT, Ghosh AK, Mitsuya H, Antimicrob Agents Chemother. 2003 Oct;47(10):3123-9. PMID:14506019

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