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dc.contributor.authorPotempa, Marc
dc.contributor.authorLee, Sook-Kyung
dc.contributor.authorYilmaz, Nese Kurt
dc.contributor.authorNalivaika, Ellen A.
dc.contributor.authorRogers, Amy
dc.contributor.authorSpielvogel, Ean
dc.contributor.authorCarter, Charles W. Jr.
dc.contributor.authorSchiffer, Celia A.
dc.contributor.authorSwanstrom, Ronald
dc.date2022-08-11T08:10:52.000
dc.date.accessioned2022-08-23T17:23:06Z
dc.date.available2022-08-23T17:23:06Z
dc.date.issued2018-11-07
dc.date.submitted2018-11-26
dc.identifier.citation<p>J Mol Biol. 2018 Nov 7. pii: S0022-2836(18)31000-3. doi: 10.1016/j.jmb.2018.10.022. [Epub ahead of print] <a href="https://doi.org/10.1016/j.jmb.2018.10.022">Link to article on publisher's site</a></p>
dc.identifier.issn0022-2836 (Linking)
dc.identifier.doi10.1016/j.jmb.2018.10.022
dc.identifier.pmid30414407
dc.identifier.urihttp://hdl.handle.net/20.500.14038/48886
dc.description.abstractRetroviral proteases (PRs) 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 that PR recognizes two different classes of substrate sequences. We analyzed the cleavage rate of over 150 combinations 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=30414407&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1016/j.jmb.2018.10.022
dc.subjectcleavage site
dc.subjectproline
dc.subjectscissile bond
dc.subjectspecificity
dc.subjectsubstrate recognition
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBiochemistry
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal Chemistry and Pharmaceutics
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectMolecular Biology
dc.subjectStructural Biology
dc.subjectVirology
dc.subjectViruses
dc.titleHIV-1 Protease Uses Bi-Specific S2/S2' Subsites to Optimize Cleavage of Two Classes of Target Sites
dc.typeJournal Article
dc.source.journaltitleJournal of molecular biology
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1030&amp;context=schiffer&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/schiffer/31
dc.identifier.contextkey13368308
refterms.dateFOA2022-08-23T17:23:06Z
html.description.abstract<p>Retroviral proteases (PRs) 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 that PR recognizes two different classes of substrate sequences. We analyzed the cleavage rate of over 150 combinations 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.</p>
dc.identifier.submissionpathschiffer/31
dc.contributor.departmentSchiffer Lab
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology


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