7Z6Z

Crystal structure of Angiotensin-1 converting enzyme N-domain in complex with fosinoprilat

PDB DOI: https://doi.org/10.2210/pdb7Z6Z/pdb

Classification: HYDROLASE
Organism(s): Homo sapiens
Expression System: Cricetulus griseus
Mutation(s): Yes

Deposited: 2022-03-14 Released: 2022-06-22
Deposition Author(s): Cozier, G.E., Acharya, K.R.
Funding Organization(s): Medical Research Council (MRC, United Kingdom)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.75 Å
R-Value Free: 0.200
R-Value Work: 0.172
R-Value Observed: 0.172

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Structural basis for the inhibition of human angiotensin-1 converting enzyme by fosinoprilat.

Cozier, G.E., Newby, E.C., Schwager, S.L.U., Isaac, R.E., Sturrock, E.D., Acharya, K.R.

(2022) FEBS J 289: 6659-6671

PubMed: 35653492 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1111/febs.16543
Primary Citation of Related Structures:
7Z6Z, 7Z70

PubMed Abstract:
Human angiotensin I-converting enzyme (ACE) has two isoforms, somatic ACE (sACE) and testis ACE (tACE). The functions of sACE are widespread, with its involvement in blood pressure regulation most extensively studied. sACE is composed of an N-domain (nACE) and a C-domain (cACE), both catalytically active but have significant structural differences, resulting in different substrate specificities. Even though ACE inhibitors are used clinically, they need much improvement because of serious side effects seen in patients (~ 25-30%) with long-term treatment due to nonselective inhibition of nACE and cACE. Investigation into the distinguishing structural features of each domain is therefore of vital importance for the development of domain-specific inhibitors with minimal side effects. Here, we report kinetic data and high-resolution crystal structures of both nACE (1.75 Å) and cACE (1.85 Å) in complex with fosinoprilat, a clinically used inhibitor. These structures allowed detailed analysis of the molecular features conferring domain selectivity by fosinoprilat. Particularly, altered hydrophobic interactions were observed to be a contributing factor. These experimental data contribute to improved understanding of the structural features that dictate ACE inhibitor domain selectivity, allowing further progress towards designing novel 2nd-generation domain-specific potent ACE inhibitors suitable for clinical administration, with a variety of potential future therapeutic benefits. DATABASE: The atomic coordinates and structure factors for nACE-fosinoprilat and cACE-fosinoprilat structures have been deposited with codes 7Z6Z and 7Z70, respectively, in the RCSB Protein Data Bank, www.pdb.org.

Organizational Affiliation

Department of Biology and Biochemistry, University of Bath, UK.

Macromolecule Content

Total Structure Weight: 151.91 kDa
Atom Count: 11,194
Modelled Residue Count: 1,208
Deposited Residue Count: 1,256
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Angiotensin-converting enzyme, soluble form	A, B	628	Homo sapiens	Mutation(s): 8 Gene Names: ACE, DCP, DCP1 EC: 3.4.15.1
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 Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P12821
Glycosylation
Glycosylation Sites: 3	Glycosylation Focus chain A Focus chain B	Go to GlyGen: P12821-1
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

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Entity ID: 2
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose	C	2		N-Glycosylation	Interactions Focus chain C Interactions & Density Focus chain C
Glycosylation Resources
GlyTouCan: G42666HT GlyCosmos: G42666HT GlyGen: G42666HT

Entity ID: 3
Molecule	Chains	Length	2D Diagram	Glycosylation	3D 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	4		N-Glycosylation	Interactions Focus chain D Interactions & Density Focus chain D
Glycosylation Resources
GlyTouCan: G32152BH GlyCosmos: G32152BH GlyGen: G32152BH

Entity ID: 4
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose	E, G	2		N-Glycosylation	Interactions Focus chain E Focus chain G Interactions & Density Focus chain E Focus chain G
Glycosylation Resources
GlyTouCan: G86851RC GlyCosmos: G86851RC GlyGen: G86851RC

Entity ID: 5
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose	F	3		N-Glycosylation	Interactions Focus chain F Interactions & Density Focus chain F
Glycosylation Resources
GlyTouCan: G21290RB GlyCosmos: G21290RB GlyGen: G21290RB

Small Molecules

Ligands 11 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
KS8 (Subject of Investigation/LOI) Query on KS8 Download Ideal Coordinates CCD File SDF format, chain EA [auth B] SDF format, chain H [auth A] MOL2 format, chain EA [auth B] MOL2 format, chain H [auth A] mmCIF format, chain EA [auth B] mmCIF format, chain H [auth A]	EA [auth B], H [auth A]	fosinoprilat C₂₃ H₃₄ N O₅ P WOIWWYDXDVSWAZ-RTWAWAEBSA-N		Interactions Focus chain EA [auth B] Focus chain H [auth A] Interactions & Density Focus chain EA [auth B] Focus chain H [auth A]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain FA [auth B] MOL2 format, chain FA [auth B] mmCIF format, chain FA [auth B]	FA [auth B]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain FA [auth B] Interactions & Density Focus chain FA [auth B]
PG4 Query on PG4 Download Ideal Coordinates CCD File SDF format, chain M [auth A] SDF format, chain U [auth A] MOL2 format, chain M [auth A] MOL2 format, chain U [auth A] mmCIF format, chain M [auth A] mmCIF format, chain U [auth A]	M [auth A], U [auth A]	TETRAETHYLENE GLYCOL C₈ H₁₈ O₅ UWHCKJMYHZGTIT-UHFFFAOYSA-N		Interactions Focus chain M [auth A] Focus chain U [auth A] Interactions & Density Focus chain M [auth A] Focus chain U [auth A]
PGE Query on PGE Download Ideal Coordinates CCD File SDF format, chain P [auth A] SDF format, chain J [auth A] SDF format, chain O [auth A] MOL2 format, chain P [auth A] MOL2 format, chain J [auth A] MOL2 format, chain O [auth A] mmCIF format, chain P [auth A] mmCIF format, chain J [auth A] mmCIF format, chain O [auth A]	J [auth A], O [auth A], P [auth A]	TRIETHYLENE GLYCOL C₆ H₁₄ O₄ ZIBGPFATKBEMQZ-UHFFFAOYSA-N		Interactions Focus chain J [auth A] Focus chain O [auth A] Focus chain P [auth A] Interactions & Density Focus chain J [auth A] Focus chain O [auth A] Focus chain P [auth A]
PEG Query on PEG Download Ideal Coordinates CCD File SDF format, chain HA [auth B] SDF format, chain T [auth A] SDF format, chain GA [auth B] SDF format, chain I [auth A] SDF format, chain K [auth A] SDF format, chain L [auth A] SDF format, chain OA [auth B] SDF format, chain S [auth A] MOL2 format, chain HA [auth B] MOL2 format, chain T [auth A] MOL2 format, chain GA [auth B] MOL2 format, chain I [auth A] MOL2 format, chain K [auth A] MOL2 format, chain L [auth A] MOL2 format, chain OA [auth B] MOL2 format, chain S [auth A] mmCIF format, chain HA [auth B] mmCIF format, chain T [auth A] mmCIF format, chain GA [auth B] mmCIF format, chain I [auth A] mmCIF format, chain K [auth A] mmCIF format, chain L [auth A] mmCIF format, chain OA [auth B] mmCIF format, chain S [auth A]	GA [auth B] HA [auth B] I [auth A] K [auth A] L [auth A] GA [auth B], HA [auth B], I [auth A], K [auth A], L [auth A], OA [auth B], S [auth A], T [auth A]	DI(HYDROXYETHYL)ETHER C₄ H₁₀ O₃ MTHSVFCYNBDYFN-UHFFFAOYSA-N		Interactions Focus chain GA [auth B] Focus chain HA [auth B] Focus chain I [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain OA [auth B] Focus chain S [auth A] Focus chain T [auth A] Interactions & Density Focus chain GA [auth B] Focus chain HA [auth B] Focus chain I [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain OA [auth B] Focus chain S [auth A] Focus chain T [auth A]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain Y [auth A] SDF format, chain QA [auth B] MOL2 format, chain Y [auth A] MOL2 format, chain QA [auth B] mmCIF format, chain Y [auth A] mmCIF format, chain QA [auth B]	QA [auth B], Y [auth A]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain QA [auth B] Focus chain Y [auth A] Interactions & Density Focus chain QA [auth B] Focus chain Y [auth A]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain BA [auth A] SDF format, chain Q [auth A] SDF format, chain SA [auth B] SDF format, chain V [auth A] SDF format, chain VA [auth B] SDF format, chain AA [auth A] SDF format, chain IA [auth B] SDF format, chain TA [auth B] SDF format, chain UA [auth B] SDF format, chain WA [auth B] SDF format, chain XA [auth B] SDF format, chain YA [auth B] MOL2 format, chain BA [auth A] MOL2 format, chain Q [auth A] MOL2 format, chain SA [auth B] MOL2 format, chain V [auth A] MOL2 format, chain VA [auth B] MOL2 format, chain AA [auth A] MOL2 format, chain IA [auth B] MOL2 format, chain TA [auth B] MOL2 format, chain UA [auth B] MOL2 format, chain WA [auth B] MOL2 format, chain XA [auth B] MOL2 format, chain YA [auth B] mmCIF format, chain BA [auth A] mmCIF format, chain Q [auth A] mmCIF format, chain SA [auth B] mmCIF format, chain V [auth A] mmCIF format, chain VA [auth B] mmCIF format, chain AA [auth A] mmCIF format, chain IA [auth B] mmCIF format, chain TA [auth B] mmCIF format, chain UA [auth B] mmCIF format, chain WA [auth B] mmCIF format, chain XA [auth B] mmCIF format, chain YA [auth B]	AA [auth A] BA [auth A] IA [auth B] Q [auth A] SA [auth B] AA [auth A], BA [auth A], IA [auth B], Q [auth A], SA [auth B], TA [auth B], UA [auth B], V [auth A], VA [auth B], WA [auth B], XA [auth B], YA [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain AA [auth A] Focus chain BA [auth A] Focus chain IA [auth B] Focus chain Q [auth A] Focus chain SA [auth B] Focus chain TA [auth B] Focus chain UA [auth B] Focus chain V [auth A] Focus chain VA [auth B] Focus chain WA [auth B] Focus chain XA [auth B] Focus chain YA [auth B] Interactions & Density Focus chain AA [auth A] Focus chain BA [auth A] Focus chain IA [auth B] Focus chain Q [auth A] Focus chain SA [auth B] Focus chain TA [auth B] Focus chain UA [auth B] Focus chain V [auth A] Focus chain VA [auth B] Focus chain WA [auth B] Focus chain XA [auth B] Focus chain YA [auth B]
ACT Query on ACT Download Ideal Coordinates CCD File SDF format, chain LA [auth B] SDF format, chain MA [auth B] SDF format, chain N [auth A] SDF format, chain NA [auth B] SDF format, chain PA [auth B] SDF format, chain W [auth A] SDF format, chain X [auth A] SDF format, chain JA [auth B] SDF format, chain KA [auth B] SDF format, chain R [auth A] MOL2 format, chain LA [auth B] MOL2 format, chain MA [auth B] MOL2 format, chain N [auth A] MOL2 format, chain NA [auth B] MOL2 format, chain PA [auth B] MOL2 format, chain W [auth A] MOL2 format, chain X [auth A] MOL2 format, chain JA [auth B] MOL2 format, chain KA [auth B] MOL2 format, chain R [auth A] mmCIF format, chain LA [auth B] mmCIF format, chain MA [auth B] mmCIF format, chain N [auth A] mmCIF format, chain NA [auth B] mmCIF format, chain PA [auth B] mmCIF format, chain W [auth A] mmCIF format, chain X [auth A] mmCIF format, chain JA [auth B] mmCIF format, chain KA [auth B] mmCIF format, chain R [auth A]	JA [auth B] KA [auth B] LA [auth B] MA [auth B] N [auth A] JA [auth B], KA [auth B], LA [auth B], MA [auth B], N [auth A], NA [auth B], PA [auth B], R [auth A], W [auth A], X [auth A]	ACETATE ION C₂ H₃ O₂ QTBSBXVTEAMEQO-UHFFFAOYSA-M		Interactions Focus chain JA [auth B] Focus chain KA [auth B] Focus chain LA [auth B] Focus chain MA [auth B] Focus chain N [auth A] Focus chain NA [auth B] Focus chain PA [auth B] Focus chain R [auth A] Focus chain W [auth A] Focus chain X [auth A] Interactions & Density Focus chain JA [auth B] Focus chain KA [auth B] Focus chain LA [auth B] Focus chain MA [auth B] Focus chain N [auth A] Focus chain NA [auth B] Focus chain PA [auth B] Focus chain R [auth A] Focus chain W [auth A] Focus chain X [auth A]
CA Query on CA Download Ideal Coordinates CCD File SDF format, chain AB [auth B] SDF format, chain CA [auth A] SDF format, chain ZA [auth B] MOL2 format, chain AB [auth B] MOL2 format, chain CA [auth A] MOL2 format, chain ZA [auth B] mmCIF format, chain AB [auth B] mmCIF format, chain CA [auth A] mmCIF format, chain ZA [auth B]	AB [auth B], CA [auth A], ZA [auth B]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain AB [auth B] Focus chain CA [auth A] Focus chain ZA [auth B] Interactions & Density Focus chain AB [auth B] Focus chain CA [auth A] Focus chain ZA [auth B]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain RA [auth B] SDF format, chain Z [auth A] MOL2 format, chain RA [auth B] MOL2 format, chain Z [auth A] mmCIF format, chain RA [auth B] mmCIF format, chain Z [auth A]	RA [auth B], Z [auth A]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain RA [auth B] Focus chain Z [auth A] Interactions & Density Focus chain RA [auth B] Focus chain Z [auth A]
NA Query on NA Download Ideal Coordinates CCD File SDF format, chain DA [auth A] MOL2 format, chain DA [auth A] mmCIF format, chain DA [auth A]	DA [auth A]	SODIUM ION Na FKNQFGJONOIPTF-UHFFFAOYSA-N		Interactions Focus chain DA [auth A] Interactions & Density Focus chain DA [auth A]