X-ray structure of HIV-1 protease in situ product complex.
HIV-1 protease is an effective target for design of different types of drugs against AIDS. HIV-1 protease is also one of the few enzymes that can cleave substrates containing both proline and nonproline residues at the cleavage site. We report here the first structure of HIV-1 protease complexed with the product peptides SQNY and PIV derived by in situ cleavage of the oligopeptide substrate SQNYPIV, within the crystals. In the structure, refined against 2.0-A resolution synchrotron data, a carboxyl oxygen of SQNY is hydrogen-bonded with the N-terminal nitrogen atom of PIV. At the same time, this proline nitrogen atom does not form any hydrogen bond with catalytic aspartates. These two observations suggest that the protonation of scissile nitrogen, during peptide bond cleavage, is by a gem-hydroxyl of the tetrahedral intermediate rather than by a catalytic aspartic acid.
Bihani
Subhash
S
Solid State Physics Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.
Das
Amit
A
Prashar
Vishal
V
Ferrer
J-L
JL
Hosur
M V
MV
D001224:Aspartic Acid / Q000737:chemistry; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry; D011487:Protein Conformation; D013379:Substrate Specificity
D009842:Oligopeptides; C092837:seryl-glutaminyl-asparaginyl-tyrosyl-prolyl-isoleucyl-valyl-glutamine; D001224:Aspartic Acid; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1