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PDBsum entry 1a94
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Hydrolase/hydrolase inhibitor
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PDB id
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1a94
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structural basis for specificity of retroviral proteases.
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Authors
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J.Wu,
J.M.Adomat,
T.W.Ridky,
J.M.Louis,
J.Leis,
R.W.Harrison,
I.T.Weber.
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Ref.
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Biochemistry, 1998,
37,
4518-4526.
[DOI no: ]
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PubMed id
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Abstract
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The Rous sarcoma virus (RSV) protease S9 variant has been engineered to exhibit
high affinity for HIV-1 protease substrates and inhibitors in order to verify
the residues deduced to be critical for the specificity differences. The variant
has 9 substitutions (S38T, I42D, I44V, M73V, A100L, V104T, R105P, G106V, and
S107N) of structurally equivalent residues from HIV-1 protease. Unlike the
wild-type enzyme, RSV S9 protease hydrolyzes peptides representing the HIV-1
protease polyprotein cleavage sites. The crystal structure of RSV S9 protease
with the inhibitor, Arg-Val-Leu-r-Phe-Glu-Ala-Nle-NH2, a reduced peptide
analogue of the HIV-1 CA-p2 cleavage site, has been refined to an R factor of
0.175 at 2.4-A resolution. The structure shows flap residues that were not
visible in the previous crystal structure of unliganded wild-type enzyme. Flap
residues 64-76 are structurally similar to residues 47-59 of HIV-1 protease.
However, residues 61-63 form unique loops at the base of the flaps. Mutational
analysis indicates that these loop residues are essential for catalytic
activity. Side chains of flap residues His 65 and Gln 63' make hydrogen bond
interactions with the inhibitor P3 amide and P4' carbonyl oxygen, respectively.
Other interactions of RSV S9 protease with the CA-p2 analogue are very similar
to those observed in the crystal structure of HIV-1 protease with the same
inhibitor. This is the first crystal structure of an avian retroviral protease
in complex with an inhibitor, and it verifies our knowledge of the molecular
basis for specificity differences between RSV and HIV-1 proteases.
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