期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 301, 期 5, 页码 1207-1220出版社
ACADEMIC PRESS LTD
DOI: 10.1006/jmbi.2000.4018
关键词
HIV-1 protease; homodimer; substrate specificity; crystallography; molecular recognition
资金
- NIGMS NIH HHS [R01 GM064347] Funding Source: Medline
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM064347] Funding Source: NIH RePORTER
The crystal structure of an actual HIV-1 protease-substrate complex is presented 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 epitope of capsid(CA)-p2 cleavage site. The substrate peptide is asymmetric in both size and charge distribution. To accommodate this asymmetry the two protease monomers adopt different conformations burying a total of 1038 Angstrom(2) Of surface area at the protease-substrate interface. The specificity for the CA-p2 substrate peptide is mainly hydrophobic, as most of the hydrogen bonds are made with the backbone of the peptide substrate. Two water molecules bridge the two monomers through the loops Gly49-Gly52 (Gly49'-Cly52') and Pro79'-Val82' (Pro79-Val82). When other complexes are compared, the mobility of these loops is correlated with the content of the P1 and P1' sites. Interdependence of the conformational changes allows the protease to exhibit its wide range of substrate specificity. (C) 2000 Academic Press.
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