8QFX

Human Angiotensin-1 converting enzyme N-domain in complex with the lactotripeptide IPP

PDB DOI: https://doi.org/10.2210/pdb8QFX/pdb

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

Deposited: 2023-09-05 Released: 2023-11-22
Deposition Author(s): Gregory, K.S., Acharya, K.R., Cozier, G.E.
Funding Organization(s): Biotechnology and Biological Sciences Research Council (BBSRC)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.60 Å
R-Value Free: 0.211
R-Value Work: 0.181

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

This is version 1.2 of the entry. See complete history.

Literature

Structural insights into the inhibitory mechanism of angiotensin-I-converting enzyme by the lactotripeptides IPP and VPP.

Gregory, K.S., Cozier, G.E., Schwager, S.L.U., Sturrock, E.D., Acharya, K.R.

(2024) FEBS Lett 598: 242-251

PubMed: 37904282 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1002/1873-3468.14768
Primary Citation of Related Structures:
8QFX, 8QHL

PubMed Abstract:
Human somatic angiotensin-1-converting enzyme (sACE) is composed of a catalytic N-(nACE) and C-domain (cACE) of similar size with different substrate specificities. It is involved in the regulation of blood pressure by converting angiotensin I to the vasoconstrictor angiotensin II and has been a major focus in the development of therapeutics for hypertension. Bioactive peptides from various sources, including milk, have been identified as natural ACE inhibitors. We report the structural basis for the role of two lacototripeptides, Val-Pro-Pro and Ile-Pro-Pro, in domain-specific inhibition of ACE using X-ray crystallography and kinetic analysis. The lactotripeptides have preference for nACE due to altered polar interactions distal to the catalytic zinc ion. Elucidating the mechanism of binding and domain selectivity of these peptides also provides important insights into the functional roles of ACE.

Organizational Affiliation

Department of Life Sciences, University of Bath, UK.

Macromolecule Content

Total Structure Weight: 303.89 kDa
Atom Count: 23,659
Modelled Residue Count: 2,445
Deposited Residue Count: 2,524
Unique protein chains: 2

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, C, D	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 Focus chain C Focus chain D	Go to GlyGen: P12821-1
Sequence Annotations Expand
Reference Sequence

Find similar proteins by: Sequence | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
ILE-PRO-PRO	E, F, G, H	3	Bos taurus	Mutation(s): 0
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

Help

Entity ID: 3
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose	I, J, L, M [auth N]	2		N-Glycosylation	Interactions Focus chain I Focus chain J Focus chain L Focus chain M [auth N] Interactions & Density Focus chain I Focus chain J Focus chain L Focus chain M [auth N]
Glycosylation Resources
GlyTouCan: G86851RC GlyCosmos: G86851RC GlyGen: G86851RC

Entity ID: 4
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	K	3		N-Glycosylation	Interactions Focus chain K Interactions & Density Focus chain K
Glycosylation Resources
GlyTouCan: G21290RB GlyCosmos: G21290RB GlyGen: G21290RB

Entity ID: 5
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose	N [auth P], O [auth R]	2		N-Glycosylation	Interactions Focus chain N [auth P] Focus chain O [auth R] Interactions & Density Focus chain N [auth P] Focus chain O [auth R]
Glycosylation Resources
GlyTouCan: G42666HT GlyCosmos: G42666HT GlyGen: G42666HT

Small Molecules

Ligands 14 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
12P Query on 12P Download Ideal Coordinates CCD File SDF format, chain T [auth A] MOL2 format, chain T [auth A] mmCIF format, chain T [auth A]	T [auth A]	DODECAETHYLENE GLYCOL C₂₄ H₅₀ O₁₃ WRZXKWFJEFFURH-UHFFFAOYSA-N		Interactions Focus chain T [auth A] Interactions & Density Focus chain T [auth A]
XPE Query on XPE Download Ideal Coordinates CCD File SDF format, chain U [auth A] SDF format, chain WB [auth D] MOL2 format, chain U [auth A] MOL2 format, chain WB [auth D] mmCIF format, chain U [auth A] mmCIF format, chain WB [auth D]	U [auth A], WB [auth D]	3,6,9,12,15,18,21,24,27-NONAOXANONACOSANE-1,29-DIOL C₂₀ H₄₂ O₁₁ DTPCFIHYWYONMD-UHFFFAOYSA-N		Interactions Focus chain U [auth A] Focus chain WB [auth D] Interactions & Density Focus chain U [auth A] Focus chain WB [auth D]
1PE Query on 1PE Download Ideal Coordinates CCD File SDF format, chain HB [auth C] MOL2 format, chain HB [auth C] mmCIF format, chain HB [auth C]	HB [auth C]	PENTAETHYLENE GLYCOL C₁₀ H₂₂ O₆ JLFNLZLINWHATN-UHFFFAOYSA-N		Interactions Focus chain HB [auth C] Interactions & Density Focus chain HB [auth C]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain FA [auth A] SDF format, chain GC [auth D] SDF format, chain HA [auth A] SDF format, chain HC [auth D] SDF format, chain IA [auth A] SDF format, chain JA [auth A] SDF format, chain JC [auth D] SDF format, chain KC [auth D] SDF format, chain PB [auth C] SDF format, chain QB [auth C] SDF format, chain RB [auth C] SDF format, chain XA [auth B] SDF format, chain ZA [auth B] MOL2 format, chain FA [auth A] MOL2 format, chain GC [auth D] MOL2 format, chain HA [auth A] MOL2 format, chain HC [auth D] MOL2 format, chain IA [auth A] MOL2 format, chain JA [auth A] MOL2 format, chain JC [auth D] MOL2 format, chain KC [auth D] MOL2 format, chain PB [auth C] MOL2 format, chain QB [auth C] MOL2 format, chain RB [auth C] MOL2 format, chain XA [auth B] MOL2 format, chain ZA [auth B] mmCIF format, chain FA [auth A] mmCIF format, chain GC [auth D] mmCIF format, chain HA [auth A] mmCIF format, chain HC [auth D] mmCIF format, chain IA [auth A] mmCIF format, chain JA [auth A] mmCIF format, chain JC [auth D] mmCIF format, chain KC [auth D] mmCIF format, chain PB [auth C] mmCIF format, chain QB [auth C] mmCIF format, chain RB [auth C] mmCIF format, chain XA [auth B] mmCIF format, chain ZA [auth B]	FA [auth A] GC [auth D] HA [auth A] HC [auth D] IA [auth A] FA [auth A], GC [auth D], HA [auth A], HC [auth D], IA [auth A], JA [auth A], JC [auth D], KC [auth D], PB [auth C], QB [auth C], RB [auth C], XA [auth B], ZA [auth B]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain FA [auth A] Focus chain GC [auth D] Focus chain HA [auth A] Focus chain HC [auth D] Focus chain IA [auth A] Focus chain JA [auth A] Focus chain JC [auth D] Focus chain KC [auth D] Focus chain PB [auth C] Focus chain QB [auth C] Focus chain RB [auth C] Focus chain XA [auth B] Focus chain ZA [auth B] Interactions & Density Focus chain FA [auth A] Focus chain GC [auth D] Focus chain HA [auth A] Focus chain HC [auth D] Focus chain IA [auth A] Focus chain JA [auth A] Focus chain JC [auth D] Focus chain KC [auth D] Focus chain PB [auth C] Focus chain QB [auth C] Focus chain RB [auth C] Focus chain XA [auth B] Focus chain ZA [auth B]
PG4 Query on PG4 Download Ideal Coordinates CCD File SDF format, chain GB [auth C] SDF format, chain XB [auth D] MOL2 format, chain GB [auth C] MOL2 format, chain XB [auth D] mmCIF format, chain GB [auth C] mmCIF format, chain XB [auth D]	GB [auth C], XB [auth D]	TETRAETHYLENE GLYCOL C₈ H₁₈ O₅ UWHCKJMYHZGTIT-UHFFFAOYSA-N		Interactions Focus chain GB [auth C] Focus chain XB [auth D] Interactions & Density Focus chain GB [auth C] Focus chain XB [auth D]
BMA Query on BMA Download Ideal Coordinates CCD File SDF format, chain EC [auth D] SDF format, chain GA [auth A] SDF format, chain OB [auth C] SDF format, chain YA [auth B] MOL2 format, chain EC [auth D] MOL2 format, chain GA [auth A] MOL2 format, chain OB [auth C] MOL2 format, chain YA [auth B] mmCIF format, chain EC [auth D] mmCIF format, chain GA [auth A] mmCIF format, chain OB [auth C] mmCIF format, chain YA [auth B]	EC [auth D], GA [auth A], OB [auth C], YA [auth B]	beta-D-mannopyranose C₆ H₁₂ O₆ WQZGKKKJIJFFOK-RWOPYEJCSA-N		Interactions Focus chain EC [auth D] Focus chain GA [auth A] Focus chain OB [auth C] Focus chain YA [auth B] Interactions & Density Focus chain EC [auth D] Focus chain GA [auth A] Focus chain OB [auth C] Focus chain YA [auth B]
FUC Query on FUC Download Ideal Coordinates CCD File SDF format, chain AB [auth B] SDF format, chain IC [auth D] MOL2 format, chain AB [auth B] MOL2 format, chain IC [auth D] mmCIF format, chain AB [auth B] mmCIF format, chain IC [auth D]	AB [auth B], IC [auth D]	alpha-L-fucopyranose C₆ H₁₂ O₅ SHZGCJCMOBCMKK-SXUWKVJYSA-N		Interactions Focus chain AB [auth B] Focus chain IC [auth D] Interactions & Density Focus chain AB [auth B] Focus chain IC [auth D]
PGE Query on PGE Download Ideal Coordinates CCD File SDF format, chain IB [auth C] SDF format, chain S [auth A] SDF format, chain SA [auth B] SDF format, chain SB [auth D] SDF format, chain W [auth A] MOL2 format, chain IB [auth C] MOL2 format, chain S [auth A] MOL2 format, chain SA [auth B] MOL2 format, chain SB [auth D] MOL2 format, chain W [auth A] mmCIF format, chain IB [auth C] mmCIF format, chain S [auth A] mmCIF format, chain SA [auth B] mmCIF format, chain SB [auth D] mmCIF format, chain W [auth A]	IB [auth C], S [auth A], SA [auth B], SB [auth D], W [auth A]	TRIETHYLENE GLYCOL C₆ H₁₄ O₄ ZIBGPFATKBEMQZ-UHFFFAOYSA-N		Interactions Focus chain IB [auth C] Focus chain S [auth A] Focus chain SA [auth B] Focus chain SB [auth D] Focus chain W [auth A] Interactions & Density Focus chain IB [auth C] Focus chain S [auth A] Focus chain SA [auth B] Focus chain SB [auth D] Focus chain W [auth A]
PEG Query on PEG Download Ideal Coordinates CCD File SDF format, chain AA [auth A] SDF format, chain CA [auth A] SDF format, chain FB [auth C] SDF format, chain NA [auth B] SDF format, chain PA [auth B] SDF format, chain QA [auth B] SDF format, chain RA [auth B] SDF format, chain V [auth A] SDF format, chain X [auth A] SDF format, chain YB [auth D] SDF format, chain ZB [auth D] MOL2 format, chain AA [auth A] MOL2 format, chain CA [auth A] MOL2 format, chain FB [auth C] MOL2 format, chain NA [auth B] MOL2 format, chain PA [auth B] MOL2 format, chain QA [auth B] MOL2 format, chain RA [auth B] MOL2 format, chain V [auth A] MOL2 format, chain X [auth A] MOL2 format, chain YB [auth D] MOL2 format, chain ZB [auth D] mmCIF format, chain AA [auth A] mmCIF format, chain CA [auth A] mmCIF format, chain FB [auth C] mmCIF format, chain NA [auth B] mmCIF format, chain PA [auth B] mmCIF format, chain QA [auth B] mmCIF format, chain RA [auth B] mmCIF format, chain V [auth A] mmCIF format, chain X [auth A] mmCIF format, chain YB [auth D] mmCIF format, chain ZB [auth D]	AA [auth A] CA [auth A] FB [auth C] NA [auth B] PA [auth B] AA [auth A], CA [auth A], FB [auth C], NA [auth B], PA [auth B], QA [auth B], RA [auth B], V [auth A], X [auth A], YB [auth D], ZB [auth D]	DI(HYDROXYETHYL)ETHER C₄ H₁₀ O₃ MTHSVFCYNBDYFN-UHFFFAOYSA-N		Interactions Focus chain AA [auth A] Focus chain CA [auth A] Focus chain FB [auth C] Focus chain NA [auth B] Focus chain PA [auth B] Focus chain QA [auth B] Focus chain RA [auth B] Focus chain V [auth A] Focus chain X [auth A] Focus chain YB [auth D] Focus chain ZB [auth D] Interactions & Density Focus chain AA [auth A] Focus chain CA [auth A] Focus chain FB [auth C] Focus chain NA [auth B] Focus chain PA [auth B] Focus chain QA [auth B] Focus chain RA [auth B] Focus chain V [auth A] Focus chain X [auth A] Focus chain YB [auth D] Focus chain ZB [auth D]
ZN (Subject of Investigation/LOI) Query on ZN Download Ideal Coordinates CCD File SDF format, chain CB [auth C] SDF format, chain KA [auth B] SDF format, chain P [auth A] SDF format, chain TB [auth D] MOL2 format, chain CB [auth C] MOL2 format, chain KA [auth B] MOL2 format, chain P [auth A] MOL2 format, chain TB [auth D] mmCIF format, chain CB [auth C] mmCIF format, chain KA [auth B] mmCIF format, chain P [auth A] mmCIF format, chain TB [auth D]	CB [auth C], KA [auth B], P [auth A], TB [auth D]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain CB [auth C] Focus chain KA [auth B] Focus chain P [auth A] Focus chain TB [auth D] Interactions & Density Focus chain CB [auth C] Focus chain KA [auth B] Focus chain P [auth A] Focus chain TB [auth D]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain AC [auth D] SDF format, chain BA [auth A] SDF format, chain BB [auth C] SDF format, chain BC [auth D] SDF format, chain CC [auth D] SDF format, chain DA [auth A] SDF format, chain EA [auth A] SDF format, chain FC [auth D] SDF format, chain JB [auth C] SDF format, chain KB [auth C] SDF format, chain LB [auth C] SDF format, chain MB [auth C] SDF format, chain OA [auth B] SDF format, chain TA [auth B] SDF format, chain UA [auth B] SDF format, chain VA [auth B] SDF format, chain Y [auth A] SDF format, chain Z [auth A] MOL2 format, chain AC [auth D] MOL2 format, chain BA [auth A] MOL2 format, chain BB [auth C] MOL2 format, chain BC [auth D] MOL2 format, chain CC [auth D] MOL2 format, chain DA [auth A] MOL2 format, chain EA [auth A] MOL2 format, chain FC [auth D] MOL2 format, chain JB [auth C] MOL2 format, chain KB [auth C] MOL2 format, chain LB [auth C] MOL2 format, chain MB [auth C] MOL2 format, chain OA [auth B] MOL2 format, chain TA [auth B] MOL2 format, chain UA [auth B] MOL2 format, chain VA [auth B] MOL2 format, chain Y [auth A] MOL2 format, chain Z [auth A] mmCIF format, chain AC [auth D] mmCIF format, chain BA [auth A] mmCIF format, chain BB [auth C] mmCIF format, chain BC [auth D] mmCIF format, chain CC [auth D] mmCIF format, chain DA [auth A] mmCIF format, chain EA [auth A] mmCIF format, chain FC [auth D] mmCIF format, chain JB [auth C] mmCIF format, chain KB [auth C] mmCIF format, chain LB [auth C] mmCIF format, chain MB [auth C] mmCIF format, chain OA [auth B] mmCIF format, chain TA [auth B] mmCIF format, chain UA [auth B] mmCIF format, chain VA [auth B] mmCIF format, chain Y [auth A] mmCIF format, chain Z [auth A]	AC [auth D] BA [auth A] BB [auth C] BC [auth D] CC [auth D] AC [auth D], BA [auth A], BB [auth C], BC [auth D], CC [auth D], DA [auth A], EA [auth A], FC [auth D], JB [auth C], KB [auth C], LB [auth C], MB [auth C], OA [auth B], TA [auth B], UA [auth B], VA [auth B], Y [auth A], Z [auth A]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain AC [auth D] Focus chain BA [auth A] Focus chain BB [auth C] Focus chain BC [auth D] Focus chain CC [auth D] Focus chain DA [auth A] Focus chain EA [auth A] Focus chain FC [auth D] Focus chain JB [auth C] Focus chain KB [auth C] Focus chain LB [auth C] Focus chain MB [auth C] Focus chain OA [auth B] Focus chain TA [auth B] Focus chain UA [auth B] Focus chain VA [auth B] Focus chain Y [auth A] Focus chain Z [auth A] Interactions & Density Focus chain AC [auth D] Focus chain BA [auth A] Focus chain BB [auth C] Focus chain BC [auth D] Focus chain CC [auth D] Focus chain DA [auth A] Focus chain EA [auth A] Focus chain FC [auth D] Focus chain JB [auth C] Focus chain KB [auth C] Focus chain LB [auth C] Focus chain MB [auth C] Focus chain OA [auth B] Focus chain TA [auth B] Focus chain UA [auth B] Focus chain VA [auth B] Focus chain Y [auth A] Focus chain Z [auth A]
ACT Query on ACT Download Ideal Coordinates CCD File SDF format, chain DC [auth D] SDF format, chain NB [auth C] SDF format, chain WA [auth B] MOL2 format, chain DC [auth D] MOL2 format, chain NB [auth C] MOL2 format, chain WA [auth B] mmCIF format, chain DC [auth D] mmCIF format, chain NB [auth C] mmCIF format, chain WA [auth B]	DC [auth D], NB [auth C], WA [auth B]	ACETATE ION C₂ H₃ O₂ QTBSBXVTEAMEQO-UHFFFAOYSA-M		Interactions Focus chain DC [auth D] Focus chain NB [auth C] Focus chain WA [auth B] Interactions & Density Focus chain DC [auth D] Focus chain NB [auth C] Focus chain WA [auth B]
CL (Subject of Investigation/LOI) Query on CL Download Ideal Coordinates CCD File SDF format, chain DB [auth C] SDF format, chain LA [auth B] SDF format, chain Q [auth A] SDF format, chain UB [auth D] MOL2 format, chain DB [auth C] MOL2 format, chain LA [auth B] MOL2 format, chain Q [auth A] MOL2 format, chain UB [auth D] mmCIF format, chain DB [auth C] mmCIF format, chain LA [auth B] mmCIF format, chain Q [auth A] mmCIF format, chain UB [auth D]	DB [auth C], LA [auth B], Q [auth A], UB [auth D]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain DB [auth C] Focus chain LA [auth B] Focus chain Q [auth A] Focus chain UB [auth D] Interactions & Density Focus chain DB [auth C] Focus chain LA [auth B] Focus chain Q [auth A] Focus chain UB [auth D]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain EB [auth C] SDF format, chain MA [auth B] SDF format, chain R [auth A] SDF format, chain VB [auth D] MOL2 format, chain EB [auth C] MOL2 format, chain MA [auth B] MOL2 format, chain R [auth A] MOL2 format, chain VB [auth D] mmCIF format, chain EB [auth C] mmCIF format, chain MA [auth B] mmCIF format, chain R [auth A] mmCIF format, chain VB [auth D]	EB [auth C], MA [auth B], R [auth A], VB [auth D]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain EB [auth C] Focus chain MA [auth B] Focus chain R [auth A] Focus chain VB [auth D] Interactions & Density Focus chain EB [auth C] Focus chain MA [auth B] Focus chain R [auth A] Focus chain VB [auth D]