How does a symmetric dimer recognize an asymmetric substrate? A substrate complex of HIV-1 protease
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2000-09-01Keywords
Amino Acid SequenceBinding Sites
Capsid
Crystallography, X-Ray
Dimerization
HIV Protease
HIV-1
Hydrogen Bonding
Models, Molecular
Peptide Fragments
Protein Conformation
Substrate Specificity
Water
Biochemistry, Biophysics, and Structural Biology
Pharmacology, Toxicology and Environmental Health
Metadata
Show full item recordAbstract
The crystal structure of an actual HIV-1 protease-substrate complex is presented at 2.0 A resolution (R-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 A(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'-Gly52') 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.Source
J Mol Biol. 2000 Sep 1;301(5):1207-20. Link to article on publisher's siteDOI
10.1006/jmbi.2000.4018Permanent Link to this Item
http://hdl.handle.net/20.500.14038/26156PubMed ID
10966816Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1006/jmbi.2000.4018