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PDBsum entry 1a8k
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Hydrolase/hydrolase inhibitor
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PDB id
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1a8k
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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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Crystallographic analysis of human immunodeficiency virus 1 protease with an analog of the conserved ca-P2 substrate -- Interactions with frequently occurring glutamic acid residue at p2' Position of substrates.
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Authors
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I.T.Weber,
J.Wu,
J.Adomat,
R.W.Harrison,
A.R.Kimmel,
E.M.Wondrak,
J.M.Louis.
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Ref.
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Eur J Biochem, 1997,
249,
523-530.
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PubMed id
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Abstract
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Human immunodeficiency virus type 1 (HIV-1) protease hydrolysis of the Gag CA-p2
cleavage site is crucial for virion maturation and is optimal at acidic pH. To
understand the processing of the CA-p2 site, we have determined the structure of
HIV-1 protease complexed with an analog of the CA-p2 site, the reduced peptide
inhibitor Arg-Val-Leu-r-Phe-Glu-Ala-Ahx-NH2 [r denotes the reduced peptide bond
and Ahx 2-aminohexanoic acid (norleucine), respectively]. The crystal structure
was refined to an R-factor of 0.17 at 0.21-nm resolution. The crystals have
nearly the same lattice as related complexes in P2(1)2(1)2(1) which have twofold
disordered inhibitor, but are in space group P2(1). and the asymmetric unit
contains two dimers of HIV-1 protease related by 180 degrees rotation. An
approximate non-crystallographic symmetry has replaced the exact crystal
symmetry resulting in well-ordered inhibitor structure. Each protease dimer
binds one ordered inhibitor molecule, but in opposite orientations. The
interactions of the inhibitor with the two dimers are very similar for the
central P2 Val to P2' Glu residues, but show more variation for the distal P3
Arg and P4' Ahx residues. Importantly, the carboxylate oxygens of Glu at P2' in
the inhibitor are within hydrogen-bonding distance of a carboxylate oxygen of
Asp30 of the protease suggesting that the two side chains share a proton. This
interaction suggests that the enzyme-substrate complex is additionally
stabilized at lower pH. The importance of this interaction is emphasized by the
absence of polymorphisms of Asp30 in the protease and variants of P2' Glu in the
critical CA-p2 cleavage site.
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