PDBsum entry 6h5x

Hydrolase

PDB id: 6h5x

Contents

Protein chains

608 a.a.

Ligands

NAG-NAG ×2

NAG-NAG-FUC ×2

NAG-FUC

NAG-NAG-BMA-FUC

FT8 ×2

XPE

PG4

EDO ×12

PGE

Metals

_ZN ×2

_CL ×2

_MG

Waters ×754

PDB id:

6h5x

Name:

Hydrolase

Title:

Crystal structure of human angiotensin-1 converting enzyme n-domain in complex with omapatrilat.

Structure:

Angiotensin-converting enzyme. Chain: a, b. Synonym: ace,dipeptidyl carboxypeptidase i,kininase ii. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ace, dcp, dcp1. Expressed in: cricetulus griseus. Expression_system_taxid: 10029

Resolution:

1.80Å R-factor: 0.165 R-free: 0.204

Authors:

G.E.Cozier,K.R.Acharya

Key ref:

G.E.Cozier et al. (2018). Molecular Basis for Multiple Omapatrilat Binding Sites within the ACE C-Domain: Implications for Drug Design. J Med Chem, 61, 10141-10154. PubMed id: 30372620 DOI: 10.1021/acs.jmedchem.8b01309

Date:

25-Jul-18 Release date: 07-Nov-18

Protein chains

P12821  (ACE_HUMAN) -  Angiotensin-converting enzyme from Homo sapiens

Seq: 1306 a.a.

Struc: 608 a.a.*

* PDB and UniProt seqs differ at 7 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.15.1 - peptidyl-dipeptidase A.
• Reaction: Release of a C-terminal dipeptide, oligopeptide-|-Xaa-Xbb, when Xaa is not Pro, and Xbb is neither Asp nor Glu. Converts angiotensin I to angiotensin II.
• Cofactor: Zn(2+)

DOI no: 10.1021/acs.jmedchem.8b01309

J Med Chem 61:10141-10154 (2018)

PubMed id: 30372620

Molecular Basis for Multiple Omapatrilat Binding Sites within the ACE C-Domain: Implications for Drug Design.

G.E.Cozier, L.B.Arendse, S.L.Schwager, E.D.Sturrock, K.R.Acharya.

ABSTRACT

Omapatrilat was designed as a vasopeptidase inhibitor with dual activity against the zinc metallopeptidases angiotensin-1 converting enzyme (ACE) and neprilysin (NEP). ACE has two homologous catalytic domains (nACE and cACE), which exhibit different substrate specificities. Here, we report high-resolution crystal structures of omapatrilat in complex with nACE and cACE and show omapatrilat has subnanomolar affinity for both domains. The structures show nearly identical binding interactions for omapatrilat in each domain, explaining the lack of domain selectivity. The cACE complex structure revealed an omapatrilat dimer occupying the cavity beyond the S₂ subsite, and this dimer had low micromolar inhibition of nACE and cACE. These results highlight residues beyond the S₂ subsite that could be exploited for domain selective inhibition. In addition, it suggests the possibility of either domain specific allosteric inhibitors that bind exclusively to the nonprime cavity or the potential for targeting specific substrates rather than completely inhibiting the enzyme.