How does a symmetric dimer recognize an asymmetric substrate? A substrate complex of HIV-1 protease

The crystal structure of an actual HIV-1 protease-substrate complex is pres ented at 2.0 Angstrom resolution (X-value of 19.7% (R-free 23.3%)) between an inactive variant (D25N) of HIV-1 protease and a long substrate peptide, Lys-Ala-Arg-Val-Leu-Ala-Glu-Ala-Met-Ser, which covers a full binding epitop e of capsid(CA)-p2 cleavage site. The substrate peptide is asymmetric in bo th size and charge distribution. To accommodate this asymmetry the two prot ease monomers adopt different conformations burying a total of 1038 Angstro m(2) Of surface area at the protease-substrate interface. The specificity f or the CA-p2 substrate peptide is mainly hydrophobic, as most of the hydrog en bonds are made with the backbone of the peptide substrate. Two water mol ecules bridge the two monomers through the loops Gly49-Gly52 (Gly49'-Cly52' ) and Pro79'-Val82' (Pro79-Val82). When other complexes are compared, the m obility of these loops is correlated with the content of the P1 and P1' sit es. Interdependence of the conformational changes allows the protease to ex hibit its wide range of substrate specificity. (C) 2000 Academic Press.