3b80: Difference between revisions

Revision as of 20:04, 21 February 2008

HIV-1 protease mutant I54V complexed with gem-diol-amine intermediate NLLTQI

OverviewOverview

HIV-1 protease (PR) is the target for several important antiviral drugs used in AIDS therapy. The drugs bind inside the active site cavity of PR where normally the viral polyprotein substrate is bound and hydrolyzed. We report two high-resolution crystal structures of wild-type PR (PRWT) and the multi-drug-resistant variant with the I54V mutation (PRI54V) in complex with a peptide at 1.46 and 1.50 A resolution, respectively. The peptide forms a gem-diol tetrahedral reaction intermediate (TI) in the crystal structures. Distinctive interactions are observed for the TI binding in the active site cavity of PRWT and PRI54V. The mutant PRI54V/TI complex has lost water-mediated hydrogen bond interactions with the amides of Ile50 and Ile50' in the flap. Hence, the structures provide insight into the mechanism of drug resistance arising from this mutation. The structures also illustrate an intermediate state in the hydrolysis reaction. One of the gem-diol hydroxide groups in the PRWT complex forms a very short (2.3 A) hydrogen bond with the outer carboxylate oxygen of Asp25. Quantum chemical calculations based on this TI structure are consistent with protonation of the inner carboxylate oxygen of Asp25', in contrast to several theoretical studies. These TI complexes and quantum calculations are discussed in relation to the chemical mechanism of the peptide bond hydrolysis catalyzed by PR.

About this StructureAbout this Structure

3B80 is a Protein complex structure of sequences from Human immunodeficiency virus 1 with and as ligands. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.

ReferenceReference

Caught in the Act: the 1.5 A resolution crystal structures of the HIV-1 protease and the I54V mutant reveal a tetrahedral reaction intermediate., Kovalevsky AY, Chumanevich AA, Liu F, Louis JM, Weber IT, Biochemistry. 2007 Dec 25;46(51):14854-64. Epub 2007 Dec 4. PMID:18052235

Page seeded by OCA on Thu Feb 21 19:04:01 2008

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 ==Overview==
-HIV-1 protease (PR) is the target for several important antiviral drugs, used in AIDS therapy. The drugs bind inside the active site cavity of PR, where normally the viral polyprotein substrate is bound and hydrolyzed. We, report two high-resolution crystal structures of wild-type PR (PRWT) and, the multi-drug-resistant variant with the I54V mutation (PRI54V) in, complex with a peptide at 1.46 and 1.50 A resolution, respectively. The, peptide forms a gem-diol tetrahedral reaction intermediate (TI) in the, crystal structures. Distinctive interactions are observed for the TI, binding in the active site cavity of PRWT and PRI54V. The mutant PRI54V/TI, complex has lost water-mediated hydrogen bond interactions with the amides, of Ile50 and Ile50' in the flap. Hence, the structures provide insight, into the mechanism of drug resistance arising from this mutation. The, structures also illustrate an intermediate state in the hydrolysis, reaction. One of the gem-diol hydroxide groups in the PRWT complex forms a, very short (2.3 A) hydrogen bond with the outer carboxylate oxygen of, Asp25. Quantum chemical calculations based on this TI structure are, consistent with protonation of the inner carboxylate oxygen of Asp25', in, contrast to several theoretical studies. These TI complexes and quantum, calculations are discussed in relation to the chemical mechanism of the, peptide bond hydrolysis catalyzed by PR.
+HIV-1 protease (PR) is the target for several important antiviral drugs used in AIDS therapy. The drugs bind inside the active site cavity of PR where normally the viral polyprotein substrate is bound and hydrolyzed. We report two high-resolution crystal structures of wild-type PR (PRWT) and the multi-drug-resistant variant with the I54V mutation (PRI54V) in complex with a peptide at 1.46 and 1.50 A resolution, respectively. The peptide forms a gem-diol tetrahedral reaction intermediate (TI) in the crystal structures. Distinctive interactions are observed for the TI binding in the active site cavity of PRWT and PRI54V. The mutant PRI54V/TI complex has lost water-mediated hydrogen bond interactions with the amides of Ile50 and Ile50' in the flap. Hence, the structures provide insight into the mechanism of drug resistance arising from this mutation. The structures also illustrate an intermediate state in the hydrolysis reaction. One of the gem-diol hydroxide groups in the PRWT complex forms a very short (2.3 A) hydrogen bond with the outer carboxylate oxygen of Asp25. Quantum chemical calculations based on this TI structure are consistent with protonation of the inner carboxylate oxygen of Asp25', in contrast to several theoretical studies. These TI complexes and quantum calculations are discussed in relation to the chemical mechanism of the peptide bond hydrolysis catalyzed by PR.
 ==About this Structure==
@@ Line 10: / Line 10: @@
 ==Reference==
-Caught in the Act: The 1.5 A Resolution Crystal Structures of the HIV-1 Protease and the I54V Mutant Reveal a Tetrahedral Reaction Intermediate., Kovalevsky AY, Chumanevich AA, Liu F, Louis JM, Weber IT, Biochemistry. 2007 Dec 25;46(51):14854-14864. Epub 2007 Dec 4. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18052235 18052235]
+Caught in the Act: the 1.5 A resolution crystal structures of the HIV-1 protease and the I54V mutant reveal a tetrahedral reaction intermediate., Kovalevsky AY, Chumanevich AA, Liu F, Louis JM, Weber IT, Biochemistry. 2007 Dec 25;46(51):14854-64. Epub 2007 Dec 4. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18052235 18052235]
 [[Category: HIV-1 retropepsin]]
 [[Category: Human immunodeficiency virus 1]]
 [[Category: Protein complex]]
-[[Category: Chumanevich, A.A.]]
+[[Category: Chumanevich, A A.]]
-[[Category: Kovalevsky, A.Y.]]
+[[Category: Kovalevsky, A Y.]]
-[[Category: Weber, I.T.]]
+[[Category: Weber, I T.]]
 [[Category: CL]]
 [[Category: NA]]
 [[Category: hydrolase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 11:25:15 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 19:04:01 2008''