2X90

Crystal structure of AnCE-enalaprilat complex

Summary for 2X90

• Entry DOI: 10.2210/pdb2x90/pdb
• Related: 1J36 1J37 1J38 2X8Y 2X8Z 2X91 2X92 2X93 2X94 2X95 2X96 2X97
• Descriptor: ANGIOTENSIN CONVERTING ENZYME, beta-D-mannopyranose-(1-6)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (7 entities in total)
• Functional Keywords: hydrolase, ace inhibitor, zinc metallopeptidase
• Biological source: DROSOPHILA MELANOGASTER (FRUIT FLY)
• Total number of polymer chains: 1
• Total formula weight: 71558.39

Authors

Akif, M.,Georgiadis, D.,Mahajan, A.,Dive, V.,Sturrock, E.D.,Isaac, R.E.,Acharya, K.R. (deposition date: 2010-03-14, release date: 2010-06-02, Last modification date: 2024-10-09)

Primary citation

Akif, M.,Georgiadis, D.,Mahajan, A.,Dive, V.,Sturrock, E.D.,Isaac, R.E.,Acharya, K.R.
High Resolution Crystal Structures of Drosophila Melanogaster Angiotensin Converting Enzyme in Complex with Novel Inhibitors and Anti- Hypertensive Drugs.
J.Mol.Biol., 400:502-, 2010

PubMed Abstract: Angiotensin I-converting enzyme (ACE), one of the central components of the renin-angiotensin system, is a key therapeutic target for the treatment of hypertension and cardiovascular disorders. Human somatic ACE (sACE) has two homologous domains (N and C). The N- and C-domain catalytic sites have different activities toward various substrates. Moreover, some of the undesirable side effects of the currently available and widely used ACE inhibitors may arise from their targeting both domains leading to defects in other pathways. In addition, structural studies have shown that although both these domains have much in common at the inhibitor binding site, there are significant differences and these are greater at the peptide binding sites than regions distal to the active site. As a model system, we have used an ACE homologue from Drosophila melanogaster (AnCE, a single domain protein with ACE activity) to study ACE inhibitor binding. In an extensive study, we present high-resolution structures for native AnCE and in complex with six known antihypertensive drugs, a novel C-domain sACE specific inhibitor, lisW-S, and two sACE domain-specific phosphinic peptidyl inhibitors, RXPA380 and RXP407 (i.e., nine structures). These structures show detailed binding features of the inhibitors and highlight subtle changes in the orientation of side chains at different binding pockets in the active site in comparison with the active site of N- and C-domains of sACE. This study provides information about the structure-activity relationships that could be utilized for designing new inhibitors with improved domain selectivity for sACE.

PubMed: 20488190
DOI: 10.1016/J.JMB.2010.05.024

Experimental method

X-RAY DIFFRACTION (1.98 Å)