4BZS

Human angiotenisn converting enzyme N-domain in complex with K-26

Summary for 4BZS

• Entry DOI: 10.2210/pdb4bzs/pdb
• Related: 4BZR
• Descriptor: ANGIOTENSIN-CONVERTING ENZYME, N-ACETYL-L-ILE-L-TYR-(R)-1-AMINO-2-(4-HYDROXYPHENYL)ETHYLPHOSPHONIC ACID, thiodiglycolic acid, ... (13 entities in total)
• Functional Keywords: hydrolase, zinc metallopeptidase, antihypertensive agent
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 150571.69

Authors

Kramer, G.J.,Mohd, A.,Schwager, S.L.U.,Masuyer, G.,Acharya, K.R.,Sturrock, E.D.,Bachmann, B.O. (deposition date: 2013-07-29, release date: 2014-02-26, Last modification date: 2024-11-13)

Primary citation

Kramer, G.J.,Mohd, A.,Schwager, S.L.U.,Masuyer, G.,Acharya, K.R.,Sturrock, E.D.,Bachmann, B.O.
Interkingdom Pharmacology of Angiotensin-I Converting Enzyme Inhibitor Phosphonates Produced by Actinomycetes
Acs Med.Chem.Lett., 5:346-, 2014

PubMed Abstract: The K-26 family of bacterial secondary metabolites are N-modified tripeptides terminated by an unusual phosphonate analog of tyrosine. These natural products, produced via three different actinomycetales, are potent inhibitors of human angiotensin-I converting enzyme (ACE). Herein we investigate the interkingdom pharmacology of the K-26 family by synthesizing these metabolites and assessing their potency as inhibitors of both the N-terminal and C-terminal domains of human ACE. In most cases, selectivity for the C-terminal domain of ACE is displayed. Co-crystallization of K-26 in both domains of human ACE reveals the structural basis of the potent inhibition and has shown an unusual binding motif that may guide future design of domain-selective inhibitors. Finally, the activity of K-26 is assayed against a cohort of microbially produced ACE relatives. In contrast to the synthetic ACE inhibitor captopril, which demonstrates broad interkingdom inhibition of ACE-like enzymes, K-26 selectively targets the eukaryotic family.

PubMed: 24900839
DOI: 10.1021/ML4004588

Experimental method

X-RAY DIFFRACTION (2.1 Å)