1A94

STRUCTURAL BASIS FOR SPECIFICITY OF RETROVIRAL PROTEASES

Summary for 1A94

• Entry DOI: 10.2210/pdb1a94/pdb
• Related PRD ID: PRD_000349
• Descriptor: PROTEASE, N-[(2R)-2-({N~5~-[amino(iminio)methyl]-L-ornithyl-L-valyl}amino)-4-methylpentyl]-L-phenylalanyl-L-alpha-glutamyl-L-alanyl-L-norleucinamide (3 entities in total)
• Functional Keywords: human immunodeficiency virus protease, rous sarcoma virus protease, protein-mediated interaction, viral maturation, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Cellular location: Gag-Pol polyprotein: Host cell membrane ; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03367
• Total number of polymer chains: 4
• Total formula weight: 44628.55

Authors

Wu, J.,Adomat, J.M.,Ridky, T.W.,Louis, J.M.,Leis, J.,Harrison, R.W.,Weber, I.T. (deposition date: 1998-04-16, release date: 1999-01-13, Last modification date: 2024-02-07)

Primary citation

Wu, J.,Adomat, J.M.,Ridky, T.W.,Louis, J.M.,Leis, J.,Harrison, R.W.,Weber, I.T.
Structural basis for specificity of retroviral proteases.
Biochemistry, 37:4518-4526, 1998

PubMed Abstract: 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.

PubMed: 9521772
DOI: 10.1021/bi972183g

Experimental method

X-RAY DIFFRACTION (2 Å)