7Q26

Crystal structure of Angiotensin-1 converting enzyme N-domain in complex with dual ACE/NEP inhibitor AD013


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.195 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

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This is version 1.3 of the entry. See complete history


Literature

Probing the Requirements for Dual Angiotensin-Converting Enzyme C-Domain Selective/Neprilysin Inhibition.

Arendse, L.B.Cozier, G.E.Eyermann, C.J.Basarab, G.S.Schwager, S.L.Chibale, K.Acharya, K.R.Sturrock, E.D.

(2022) J Med Chem 65: 3371-3387

  • DOI: https://doi.org/10.1021/acs.jmedchem.1c01924
  • Primary Citation of Related Structures:  
    7Q24, 7Q25, 7Q26, 7Q27, 7Q28, 7Q29

  • PubMed Abstract: 

    Selective inhibition of the angiotensin-converting enzyme C-domain (cACE) and neprilysin (NEP), leaving the ACE N-domain (nACE) free to degrade bradykinin and other peptides, has the potential to provide the potent antihypertensive and cardioprotective benefits observed for nonselective dual ACE/NEP inhibitors, such as omapatrilat, without the increased risk of adverse effects. We have synthesized three 1-carboxy-3-phenylpropyl dipeptide inhibitors with nanomolar potency based on the previously reported C-domain selective ACE inhibitor lisinopril-tryptophan (LisW) to probe the structural requirements for potent dual cACE/NEP inhibition. Here we report the synthesis, enzyme kinetic data, and high-resolution crystal structures of these inhibitors bound to nACE and cACE, providing valuable insight into the factors driving potency and selectivity. Overall, these results highlight the importance of the interplay between the S 1 ' and S 2 ' subsites for ACE domain selectivity, providing guidance for future chemistry efforts toward the development of dual cACE/NEP inhibitors.


  • Organizational Affiliation

    Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town 7925, South Africa.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Angiotensin-converting enzyme
A, B
629Homo sapiensMutation(s): 8 
Gene Names: ACEDCPDCP1
EC: 3.2.1 (PDB Primary Data), 3.4.15.1 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P12821 (Homo sapiens)
Explore P12821 
Go to UniProtKB:  P12821
PHAROS:  P12821
GTEx:  ENSG00000159640 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP12821
Glycosylation
Glycosylation Sites: 3Go to GlyGen: P12821-1
Sequence Annotations
Expand
  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
C
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose
D, F
4N-Glycosylation
Glycosylation Resources
GlyTouCan:  G32152BH
GlyCosmos:  G32152BH
GlyGen:  G32152BH
Entity ID: 4
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose
E, G
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G86851RC
GlyCosmos:  G86851RC
GlyGen:  G86851RC
Small Molecules
Ligands 12 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
8JV (Subject of Investigation/LOI)
Query on 8JV

Download Ideal Coordinates CCD File 
H [auth A],
R [auth B]
(2~{S},5~{R})-5-(4-methylphenyl)-1-[2-[[(2~{S})-1-oxidanyl-1-oxidanylidene-4-phenyl-butan-2-yl]amino]ethanoyl]pyrrolidine-2-carboxylic acid
C24 H28 N2 O5
WVLQTFUZRYRSBE-HBMCJLEFSA-N
PE8
Query on PE8

Download Ideal Coordinates CCD File 
U [auth B]3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL
C16 H34 O9
GLZWNFNQMJAZGY-UHFFFAOYSA-N
1PE
Query on 1PE

Download Ideal Coordinates CCD File 
AA [auth B],
N [auth A]
PENTAETHYLENE GLYCOL
C10 H22 O6
JLFNLZLINWHATN-UHFFFAOYSA-N
NAG
Query on NAG

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S [auth B]2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
PG4
Query on PG4

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Y [auth B]TETRAETHYLENE GLYCOL
C8 H18 O5
UWHCKJMYHZGTIT-UHFFFAOYSA-N
PGE
Query on PGE

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T [auth B]TRIETHYLENE GLYCOL
C6 H14 O4
ZIBGPFATKBEMQZ-UHFFFAOYSA-N
PEG
Query on PEG

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BA [auth B],
O [auth A]
DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
ZN
Query on ZN

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I [auth A],
V [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
EDO
Query on EDO

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P [auth A],
Q [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
ACT
Query on ACT

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L [auth A],
M [auth A],
Z [auth B]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
CL
Query on CL

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J [auth A],
W [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
MG
Query on MG

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K [auth A],
X [auth B]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
8JV BindingDB:  7Q26 Ki: min: 440, max: 3400 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.195 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.888α = 88.634
b = 77.1β = 64.177
c = 82.621γ = 74.787
Software Package:
Software NamePurpose
PHENIXrefinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 8JVClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Medical Research Council (MRC, United Kingdom)United KingdomMR/M026647/1

Revision History  (Full details and data files)

  • Version 1.0: 2022-02-16
    Type: Initial release
  • Version 1.1: 2022-03-09
    Changes: Database references
  • Version 1.2: 2024-01-31
    Changes: Data collection, Refinement description
  • Version 1.3: 2024-11-20
    Changes: Structure summary