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PDBsum entry 2x91

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Hydrolase PDB id
2x91
Jmol
Contents
Protein chain
595 a.a.
Ligands
LPR
EPE ×3
NAG-NAG-BMA-BMA-
MAN
NAG ×2
MAN
Metals
_ZN
Waters ×431

References listed in PDB file
Key reference
Title High resolution crystal structures of drosophila melanogaster angiotensin converting enzyme in complex with novel inhibitors and anti-Hypertensive drugs.
Authors M.Akif, D.Georgiadis, A.Mahajan, V.Dive, E.D.Sturrock, R.E.Isaac, K.R.Acharya.
Ref. J Mol Biol, 2010, 400, 502-517. [DOI no: 10.1016/j.jmb.2010.05.024]
PubMed id 20488190
Abstract
Angiotensin-I converting enzyme (ACE), one of the central components of 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 the wrong domain leading to defects in other signalling 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 homolog 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 anti-hypertensive 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 which could be utilized for designing new inhibitors with improved domain selectivity for sACE.
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