Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril
| dc.contributor.author | Watermeyer, Jean M | |
| dc.contributor.author | Kröger, Wendy L | |
| dc.contributor.author | O'Neill, Hester G | |
| dc.contributor.author | Sewell, Trevor B | |
| dc.contributor.author | Sturrock, Edward D | |
| dc.date.accessioned | 2016-07-27T13:55:10Z | |
| dc.date.available | 2016-07-27T13:55:10Z | |
| dc.date.issued | 2010 | |
| dc.date.updated | 2016-07-12T14:59:36Z | |
| dc.description.abstract | Human ACE (angiotensin-converting enzyme) (EC 3.4.15.1) is an important drug target because of its role in the regulation of blood pressure via the renin–angiotensin–aldosterone system. Somatic ACE comprises two homologous domains, the differing substrate preferences of which present a new avenue for domainselective inhibitor design. We have co-crystallized lisW-S, a Cdomain-selective derivative of the drug lisinopril, with human testis ACE and determined a structure using X-ray crystallography to a resolution of 2.30 Å (1 Å = 0.1 nm). In this structure, lisW-S is seen to have a similar binding mode to its parent compound lisinopril, but the P2 tryptophan moiety takes a different conformation to that seen in other inhibitors having a tryptophan residue in this position. We have examined further the domain-specific interactions of this inhibitor by mutating Cdomain-specific active-site residues to their N domain equivalents, then assessing the effect of the mutation on inhibition by lisWS using a fluorescence-based assay. Kinetics analysis shows a 258-fold domain-selectivity that is largely due to the co-operative effect of C-domain-specific residues in the S2 subsite. The high affinity and selectivity of this inhibitor make it a good lead candidate for cardiovascular drug development. | en_ZA |
| dc.identifier | http://dx.doi.org/10.1042/BJ20100056 | |
| dc.identifier.apacitation | Watermeyer, J. M., Kröger, W. L., O'Neill, H. G., Sewell, T. B., & Sturrock, E. D. (2010). Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril. <i>Biochemical Journal</i>, http://hdl.handle.net/11427/20907 | en_ZA |
| dc.identifier.chicagocitation | Watermeyer, Jean M, Wendy L Kröger, Hester G O'Neill, Trevor B Sewell, and Edward D Sturrock "Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril." <i>Biochemical Journal</i> (2010) http://hdl.handle.net/11427/20907 | en_ZA |
| dc.identifier.citation | Watermeyer, J. M., Kröger, W. L., O'Neill, H. G., Sewell, B. T., & Sturrock, E. D. (2010). Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril. Biochemical Journal, 428(1), 67-74. | en_ZA |
| dc.identifier.issn | 0264-6021 | en_ZA |
| dc.identifier.ris | TY - Journal Article AU - Watermeyer, Jean M AU - Kröger, Wendy L AU - O'Neill, Hester G AU - Sewell, Trevor B AU - Sturrock, Edward D AB - Human ACE (angiotensin-converting enzyme) (EC 3.4.15.1) is an important drug target because of its role in the regulation of blood pressure via the renin–angiotensin–aldosterone system. Somatic ACE comprises two homologous domains, the differing substrate preferences of which present a new avenue for domainselective inhibitor design. We have co-crystallized lisW-S, a Cdomain-selective derivative of the drug lisinopril, with human testis ACE and determined a structure using X-ray crystallography to a resolution of 2.30 Å (1 Å = 0.1 nm). In this structure, lisW-S is seen to have a similar binding mode to its parent compound lisinopril, but the P2 tryptophan moiety takes a different conformation to that seen in other inhibitors having a tryptophan residue in this position. We have examined further the domain-specific interactions of this inhibitor by mutating Cdomain-specific active-site residues to their N domain equivalents, then assessing the effect of the mutation on inhibition by lisWS using a fluorescence-based assay. Kinetics analysis shows a 258-fold domain-selectivity that is largely due to the co-operative effect of C-domain-specific residues in the S2 subsite. The high affinity and selectivity of this inhibitor make it a good lead candidate for cardiovascular drug development. DA - 2010 DB - OpenUCT DP - University of Cape Town J1 - Biochemical Journal LK - https://open.uct.ac.za PB - University of Cape Town PY - 2010 SM - 0264-6021 T1 - Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril TI - Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril UR - http://hdl.handle.net/11427/20907 ER - | en_ZA |
| dc.identifier.uri | http://hdl.handle.net/11427/20907 | |
| dc.identifier.vancouvercitation | Watermeyer JM, Kröger WL, O'Neill HG, Sewell TB, Sturrock ED. Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril. Biochemical Journal. 2010; http://hdl.handle.net/11427/20907. | en_ZA |
| dc.language | eng | en_ZA |
| dc.publisher | Portland Press | en_ZA |
| dc.publisher.institution | University of Cape Town | |
| dc.source | Biochemical Journal | en_ZA |
| dc.source.uri | http://www.biochemj.org/ | |
| dc.subject.other | Angiotensin-converting enzyme (ACE) inhibitor, Domain-selective inhibition, Lisinopril, Testis | |
| dc.title | Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril | en_ZA |
| dc.type | Journal Article | en_ZA |
| uct.type.filetype | Text | |
| uct.type.filetype | Image | |
| uct.type.publication | Research | en_ZA |
| uct.type.resource | Article | en_ZA |