1UZE

Complex of the anti-hypertensive drug enalaprilat and the human testicular angiotensin I-converting enzyme

Summary for 1UZE

• Entry DOI: 10.2210/pdb1uze/pdb
• Related: 1O86 1O8A 1UZF
• Descriptor: ANGIOTENSIN CONVERTING ENZYME, GLYCINE, ZINC ION, ... (6 entities in total)
• Functional Keywords: metalloprotease, angiotensin converting enzyme, inhibitor, enalaprilat, zinc dependant peptidase, anti-hypertensive drug
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 68628.70

Authors

Natesh, R.,Schwager, S.L.U.,Evans, H.R.,Sturrock, E.D.,Acharya, K.R. (deposition date: 2004-03-11, release date: 2004-07-16, Last modification date: 2024-10-23)

Primary citation

Natesh, R.,Schwager, S.L.U.,Evans, H.R.,Sturrock, E.D.,Acharya, K.R.
Structural Details on the Binding of Antihypertensive Drugs Captopril and Enalaprilat to Human Testicular Angiotensin I-Converting Enzyme
Biochemistry, 43:8718-, 2004

PubMed Abstract: Angiotensin converting enzyme (ACE) plays a critical role in the circulating or endocrine renin-angiotensin system (RAS) as well as the local regulation that exists in tissues such as the myocardium and skeletal muscle. Here we report the high-resolution crystal structures of testis ACE (tACE) in complex with the first successfully designed ACE inhibitor captopril and enalaprilat, the Phe-Ala-Pro analogue. We have compared these structures with the recently reported structure of a tACE-lisinopril complex [Natesh et al. (2003) Nature 421, 551-554]. The analyses reveal that all three inhibitors make direct interactions with the catalytic Zn(2+) ion at the active site of the enzyme: the thiol group of captopril and the carboxylate group of enalaprilat and lisinopril. Subtle differences are also observed at other regions of the binding pocket. These are compared with N-domain models and discussed with reference to published biochemical data. The chloride coordination geometries of the three structures are discussed and compared with other ACE analogues. It is anticipated that the molecular details provided by these structures will be used to improve the binding and/or the design of new, more potent domain-specific inhibitors of ACE that could serve as new generation antihypertensive drugs.

PubMed: 15236580
DOI: 10.1021/BI049480N

Experimental method

X-RAY DIFFRACTION (1.82 Å)