1dw6: Difference between revisions

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STRUCTURAL AND KINETIC ANALYSIS OF DRUG RESISTANT MUTANTS OF HIV-1 PROTEASE

OverviewOverview

Mutants of HIV-1 protease that are commonly selected on exposure to, different drugs, V82S, G48V, N88D and L90M, showed reduced catalytic, activity compared to the wild-type protease on cleavage site peptides, CA-p2, p6pol-PR and PR-RT, critical for viral maturation. Mutant V82S is, the least active (2-20% of wild-type protease), mutants N88D, R8Q, and, L90M exhibit activities ranging from 20 to 40% and G48V from 50 to 80% of, the wild-type activity. In contrast, D30N is variable in its activity on, different substrates (10-110% of wild-type), with the PR-RT site being the, most affected. Mutants K45I and M46L, usually selected in combination with, other mutations, showed activities that are similar to (60-110%) or, greater than (110-530%) wild-type, respectively. No direct relationship, was observed between catalytic activity, inhibition, and structural, stability. The mutants D30N and V82S were similar to wild-type protease in, their stability toward urea denaturation, while R8Q, G48V, and L90M showed, 1.5 to 2.7-fold decreased stability, and N88D and K45I showed 1.6 to, 1.7-fold increased stability. The crystal structures of R8Q, K45I and L90M, mutants complexed with a CA-p2 analog inhibitor were determined at 2.0, 1.55 and 1.88 A resolution, respectively, and compared to the wild-type, structure. The intersubunit hydrophobic contacts observed in the crystal, structures are in good agreement with the relative structural stability of, the mutant proteases. All these results suggest that viral resistance does, not arise by a single mechanism.

About this StructureAbout this Structure

1DW6 is a Single protein structure of sequence from Human immunodeficiency virus 1. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.

ReferenceReference

Structural and kinetic analysis of drug resistant mutants of HIV-1 protease., Mahalingam B, Louis JM, Reed CC, Adomat JM, Krouse J, Wang YF, Harrison RW, Weber IT, Eur J Biochem. 1999 Jul;263(1):238-45. PMID:10429209

Page seeded by OCA on Fri Feb 15 15:41:02 2008

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OCA

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+[[Image:1dw6.jpg|left|200px]]<br /><applet load="1dw6" size="350" color="white" frame="true" align="right" spinBox="true"
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 '''STRUCTURAL AND KINETIC ANALYSIS OF DRUG RESISTANT MUTANTS OF HIV-1 PROTEASE'''<br />
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 ==About this Structure==
-DW6 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]. 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=1DW6 OCA].
+DW6 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]. 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=1DW6 OCA].
 ==Reference==
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 [[Category: mutant]]
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