From Proteopedia
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| - | [[Image:2avm.gif|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_2avm| PDB=2avm | SCENE= }} | | {{STRUCTURE_2avm| PDB=2avm | SCENE= }} |
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| - | '''Kinetics, stability, and structural changes in high resolution crystal structures of HIV-1 protease with drug resistant mutations L24I, I50V, AND G73S'''
| + | ===Kinetics, stability, and structural changes in high resolution crystal structures of HIV-1 protease with drug resistant mutations L24I, I50V, AND G73S=== |
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| - | ==Overview==
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| - | The crystal structures, dimer stabilities, and kinetics have been analyzed for wild-type human immunodeficiency virus type 1 (HIV-1) protease (PR) and resistant mutants PR(L24I), PR(I50V), and PR(G73S) to gain insight into the molecular basis of drug resistance. The mutations lie in different structural regions. Mutation I50V alters a residue in the flexible flap that interacts with the inhibitor, L24I alters a residue adjacent to the catalytic Asp25, and G73S lies at the protein surface far from the inhibitor-binding site. PR(L24I) and PR(I50V), showed a 4% and 18% lower k(cat)/K(m), respectively, relative to PR. The relative k(cat)/K(m) of PR(G73S) varied from 14% to 400% when assayed using different substrates. Inhibition constants (K(i)) of the antiviral drug indinavir for the reaction catalyzed by the mutant enzymes were about threefold and 50-fold higher for PR(L24I) and PR(I50V), respectively, relative to PR and PR(G73S). The dimer dissociation constant (K(d)) was estimated to be approximately 20 nM for both PR(L24I) and PR(I50V), and below 5 nM for PR(G73S) and PR. Crystal structures of the mutants PR(L24I), PR(I50V) and PR(G73S) were determined in complexes with indinavir, or the p2/NC substrate analog at resolutions of 1.10-1.50 Angstrom. Each mutant revealed distinct structural changes relative to PR. The mutated residues in PR(L24I) and PR(I50V) had reduced intersubunit contacts, consistent with the increased K(d) for dimer dissociation. Relative to PR, PR(I50V) had fewer interactions of Val50 with inhibitors, in agreement with the dramatically increased K(i). The distal mutation G73S introduced new hydrogen bond interactions that can transmit changes to the substrate-binding site and alter catalytic activity. Therefore, the structural alterations observed for drug-resistant mutations were in agreement with kinetic and stability changes. | + | The line below this paragraph, {{ABSTRACT_PUBMED_16277992}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 16277992 is the PubMed ID number. |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Non-active site mutants.]] | | [[Category: Non-active site mutants.]] |
| | [[Category: Substrate analog]] | | [[Category: Substrate analog]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 19:31:34 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 09:22:30 2008'' |
Revision as of 06:22, 28 July 2008
Template:STRUCTURE 2avm
Kinetics, stability, and structural changes in high resolution crystal structures of HIV-1 protease with drug resistant mutations L24I, I50V, AND G73S
Template:ABSTRACT PUBMED 16277992
About this Structure
2AVM is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.
Reference
Kinetic, stability, and structural changes in high-resolution crystal structures of HIV-1 protease with drug-resistant mutations L24I, I50V, and G73S., Liu F, Boross PI, Wang YF, Tozser J, Louis JM, Harrison RW, Weber IT, J Mol Biol. 2005 Dec 9;354(4):789-800. Epub 2005 Oct 21. PMID:16277992
Page seeded by OCA on Mon Jul 28 09:22:30 2008
