The structure of testis angiotensin-converting enzyme in complex with the C domain-specific inhibitor RXPA380.
| dc.contributor.author | Corradi, Hazel R | |
| dc.contributor.author | Chitapi, Itai | |
| dc.contributor.author | Sewell, Trevor B | |
| dc.contributor.author | Georgiadis, Dimitris | |
| dc.contributor.author | Dive, Vincent | |
| dc.contributor.author | Sturrock, Edward D | |
| dc.contributor.author | Acharya, Ravi K | |
| dc.date.accessioned | 2016-07-15T13:04:27Z | |
| dc.date.available | 2016-07-15T13:04:27Z | |
| dc.date.issued | 2007 | |
| dc.date.updated | 2016-07-15T13:02:30Z | |
| dc.description.abstract | Angiotensin I-converting enzyme (ACE) is central to the regulation of the renin-angiotensin system and is a key therapeutic target for combating hypertension and related cardiovascular diseases. Currently available drugs bind both active sites of its two homologous domains, although it is now understood that these domains function differently in vivo. The recently solved crystal structures of both domains (N and C) open the door to new domain-specific inhibitor design, taking advantage of the differences between these two large active sites. Here we present the first crystal structure at a resolution of 2.25 Å of testis ACE (identical to the C domain of somatic ACE) with the highly C-domain-specific phosphinic inhibitor, RXPA380. Testis ACE retains the same conformation as seen in previously determined inhibitor complexes, but the RXPA380 central backbone conformation is more similar to that seen for the inhibitor captopril than enalaprilat. The RXPA380 molecule occupies more subsites of the testis ACE active site than the previously determined inhibitors and possesses bulky moieties that extend into the S2′ and S2 subsites. Thus the high affinity of RXPA380 for the testis ACE/somatic ACE C domain is explained by the interaction of these bulky moieties with residues unique to these domains, specifically Phe 391, Val 379, and Val 380, that are not found in the N domain. The characterization of the extended active site and the binding of a potent C-domain-selective inhibitor provide the first structural data for the design of truly domain-specific pharmacophores. | en_ZA |
| dc.identifier | http://dx.doi.org/10.1021/bi700275e | |
| dc.identifier.apacitation | Corradi, H. R., Chitapi, I., Sewell, T. B., Georgiadis, D., Dive, V., Sturrock, E. D., & Acharya, R. K. (2007). The structure of testis angiotensin-converting enzyme in complex with the C domain-specific inhibitor RXPA380. <i>Biochemistry</i>, http://hdl.handle.net/11427/20383 | en_ZA |
| dc.identifier.chicagocitation | Corradi, Hazel R, Itai Chitapi, Trevor B Sewell, Dimitris Georgiadis, Vincent Dive, Edward D Sturrock, and Ravi K Acharya "The structure of testis angiotensin-converting enzyme in complex with the C domain-specific inhibitor RXPA380." <i>Biochemistry</i> (2007) http://hdl.handle.net/11427/20383 | en_ZA |
| dc.identifier.citation | Corradi, H. R., Chitapi, I., Sewell, B. T., Georgiadis, D., Dive, V., Sturrock, E. D., & Acharya, K. R. (2007). The structure of testis angiotensin-converting enzyme in complex with the C domain-specific inhibitor RXPA380. Biochemistry, 46(18), 5473-5478. | en_ZA |
| dc.identifier.ris | TY - Journal Article AU - Corradi, Hazel R AU - Chitapi, Itai AU - Sewell, Trevor B AU - Georgiadis, Dimitris AU - Dive, Vincent AU - Sturrock, Edward D AU - Acharya, Ravi K AB - Angiotensin I-converting enzyme (ACE) is central to the regulation of the renin-angiotensin system and is a key therapeutic target for combating hypertension and related cardiovascular diseases. Currently available drugs bind both active sites of its two homologous domains, although it is now understood that these domains function differently in vivo. The recently solved crystal structures of both domains (N and C) open the door to new domain-specific inhibitor design, taking advantage of the differences between these two large active sites. Here we present the first crystal structure at a resolution of 2.25 Å of testis ACE (identical to the C domain of somatic ACE) with the highly C-domain-specific phosphinic inhibitor, RXPA380. Testis ACE retains the same conformation as seen in previously determined inhibitor complexes, but the RXPA380 central backbone conformation is more similar to that seen for the inhibitor captopril than enalaprilat. The RXPA380 molecule occupies more subsites of the testis ACE active site than the previously determined inhibitors and possesses bulky moieties that extend into the S2′ and S2 subsites. Thus the high affinity of RXPA380 for the testis ACE/somatic ACE C domain is explained by the interaction of these bulky moieties with residues unique to these domains, specifically Phe 391, Val 379, and Val 380, that are not found in the N domain. The characterization of the extended active site and the binding of a potent C-domain-selective inhibitor provide the first structural data for the design of truly domain-specific pharmacophores. DA - 2007 DB - OpenUCT DP - University of Cape Town J1 - Biochemistry LK - https://open.uct.ac.za PB - University of Cape Town PY - 2007 T1 - The structure of testis angiotensin-converting enzyme in complex with the C domain-specific inhibitor RXPA380 TI - The structure of testis angiotensin-converting enzyme in complex with the C domain-specific inhibitor RXPA380 UR - http://hdl.handle.net/11427/20383 ER - | en_ZA |
| dc.identifier.uri | http://hdl.handle.net/11427/20383 | |
| dc.identifier.uri | http://pubs.acs.org/doi/abs/10.1021/bi700275e | |
| dc.identifier.vancouvercitation | Corradi HR, Chitapi I, Sewell TB, Georgiadis D, Dive V, Sturrock ED, et al. The structure of testis angiotensin-converting enzyme in complex with the C domain-specific inhibitor RXPA380. Biochemistry. 2007; http://hdl.handle.net/11427/20383. | en_ZA |
| dc.language | eng | en_ZA |
| dc.publisher | American Chemical Society | en_ZA |
| dc.publisher.department | Institute of Infectious Disease and Molecular Medicine | en_ZA |
| dc.publisher.faculty | Faculty of Health Sciences | en_ZA |
| dc.publisher.institution | University of Cape Town | |
| dc.source | Biochemistry | en_ZA |
| dc.source.uri | http://pubs.acs.org/doi/abs/10.1021/bi700275e | |
| dc.subject.other | Testis Angiotensin-Converting Enzyme | |
| dc.title | The structure of testis angiotensin-converting enzyme in complex with the C domain-specific inhibitor RXPA380. | 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 |