HIV-1 Protease Uses Bi-Specific S2/S2′ Subsites to Optimize Cleavage of Two Classes of Target Sites
| Autor: | Charles W. Carter, Ean Spielvogel, Marc Potempa, Celia A. Schiffer, Ronald Swanstrom, Amy Rogers, Nese Kurt Yilmaz, Ellen A. Nalivaika, Sook Kyung Lee |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine Steric effects Conformational change Proline Protein Conformation Stereochemistry Cleavage (embryo) Article Substrate Specificity 03 medical and health sciences Scissile bond HIV Protease HIV-1 protease Structural Biology Side chain Amino Acids Molecular Biology 030304 developmental biology chemistry.chemical_classification 0303 health sciences Binding Sites 030102 biochemistry & molecular biology biology 030302 biochemistry & molecular biology 3. Good health Amino acid Kinetics 030104 developmental biology chemistry Proteolysis HIV-1 biology.protein Hydrophobic and Hydrophilic Interactions |
| Zdroj: | Journal of Molecular Biology. 430:5182-5195 |
| ISSN: | 0022-2836 |
| DOI: | 10.1016/j.jmb.2018.10.022 |
| Popis: | Retroviral proteases (PR) have a unique specificity that allows cleavage of sites with or without a P1’ proline. A P1’ proline is required at the MA/CA cleavage site due to its role in a post-cleavage conformational change in the capsid protein. However, the HIV-1 PR prefers to have large hydrophobic amino acids flanking the scissile bond, suggesting PR recognizes two different classes of substrate sequences. We analyzed the cleavage rate of over 150 iterations of six different HIV-1 cleavage sites to explore rate determinants of cleavage. We found that cleavage rates are strongly influenced by the two amino acids flanking the amino acids at the scissile bond (P2-P1/P1’-P2’), with two complementary sets of rules. When P1’ is proline, the P2 side chain interacts with a polar region in the S2 subsite of the PR, while the P2’ amino acid interacts with a hydrophobic region of the S2’ subsite. When P1’ is not proline, the orientations of the P2 and P2’ side chains with respect to the scissile bond are reversed; P2 residues interact with a hydrophobic face of the S2 subsite while the P2’ amino acid usually engages hydrophilic amino acids in the S2’ subsite. These results reveal that the HIV-1 PR has evolved bi-functional S2 and S2’ subsites to accommodate the steric effects imposed by a P1’ proline on the orientation of P2 and P2’ substrate side chains. These results also suggest a new strategy for inhibitor design to engage the multiple specificities in these subsites. |
| Databáze: | OpenAIRE |
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