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- PDB-7q25: Crystal structure of Angiotensin-1 converting enzyme N-domain in ... -

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Basic information

Entry
Database: PDB / ID: 7q25
TitleCrystal structure of Angiotensin-1 converting enzyme N-domain in complex with dual ACE/NEP inhibitor AD012
ComponentsAngiotensin-converting enzyme
KeywordsHYDROLASE / Angiotensin-1 converting enzyme / Dual inhibitor / NEP / Metalloprotease
Function / homology
Function and homology information


mononuclear cell proliferation / cell proliferation in bone marrow / bradykinin receptor binding / tripeptidyl-peptidase activity / exopeptidase activity / regulation of angiotensin metabolic process / substance P catabolic process / peptidyl-dipeptidase A / regulation of renal output by angiotensin / positive regulation of peptidyl-cysteine S-nitrosylation ...mononuclear cell proliferation / cell proliferation in bone marrow / bradykinin receptor binding / tripeptidyl-peptidase activity / exopeptidase activity / regulation of angiotensin metabolic process / substance P catabolic process / peptidyl-dipeptidase A / regulation of renal output by angiotensin / positive regulation of peptidyl-cysteine S-nitrosylation / negative regulation of calcium ion import / response to laminar fluid shear stress / positive regulation of systemic arterial blood pressure / negative regulation of gap junction assembly / metallodipeptidase activity / cellular response to aldosterone / hormone catabolic process / bradykinin catabolic process / angiogenesis involved in coronary vascular morphogenesis / response to thyroid hormone / negative regulation of D-glucose import / vasoconstriction / neutrophil mediated immunity / regulation of smooth muscle cell migration / regulation of hematopoietic stem cell proliferation / hormone metabolic process / antigen processing and presentation of peptide antigen via MHC class I / mitogen-activated protein kinase binding / embryo development ending in birth or egg hatching / chloride ion binding / mitogen-activated protein kinase kinase binding / positive regulation of neurogenesis / heterocyclic compound binding / lung alveolus development / arachidonate secretion / post-transcriptional regulation of gene expression / eating behavior / peptide catabolic process / heart contraction / response to dexamethasone / regulation of heart rate by cardiac conduction / regulation of systemic arterial blood pressure by renin-angiotensin / blood vessel remodeling / hematopoietic stem cell differentiation / regulation of vasoconstriction / peptidyl-dipeptidase activity / animal organ regeneration / amyloid-beta metabolic process / angiotensin maturation / Metabolism of Angiotensinogen to Angiotensins / positive regulation of vasoconstriction / carboxypeptidase activity / sperm midpiece / blood vessel diameter maintenance / basal plasma membrane / response to nutrient levels / kidney development / angiotensin-activated signaling pathway / female pregnancy / cellular response to glucose stimulus / brush border membrane / regulation of synaptic plasticity / metalloendopeptidase activity / regulation of blood pressure / male gonad development / metallopeptidase activity / peptidase activity / actin binding / spermatogenesis / endopeptidase activity / response to lipopolysaccharide / lysosome / response to hypoxia / calmodulin binding / endosome / positive regulation of apoptotic process / response to xenobiotic stimulus / external side of plasma membrane / negative regulation of gene expression / proteolysis / extracellular space / extracellular exosome / zinc ion binding / extracellular region / plasma membrane
Similarity search - Function
Peptidase M2, peptidyl-dipeptidase A / Angiotensin-converting enzyme / Peptidase family M2 domain profile. / Neutral zinc metallopeptidases, zinc-binding region signature.
Similarity search - Domain/homology
Chem-8J9 / ACETATE ION / DI(HYDROXYETHYL)ETHER / Angiotensin-converting enzyme
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsCozier, G.E. / Acharya, K.R.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MR/M026647/1 United Kingdom
CitationJournal: J.Med.Chem. / Year: 2022
Title: Probing the Requirements for Dual Angiotensin-Converting Enzyme C-Domain Selective/Neprilysin Inhibition.
Authors: Arendse, L.B. / Cozier, G.E. / Eyermann, C.J. / Basarab, G.S. / Schwager, S.L. / Chibale, K. / Acharya, K.R. / Sturrock, E.D.
History
DepositionOct 23, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 16, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 9, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Angiotensin-converting enzyme
B: Angiotensin-converting enzyme
hetero molecules


Theoretical massNumber of molelcules
Total (without water)150,67230
Polymers145,2132
Non-polymers5,45928
Water14,286793
1
A: Angiotensin-converting enzyme
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,59117
Polymers72,6071
Non-polymers2,98416
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Angiotensin-converting enzyme
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,08113
Polymers72,6071
Non-polymers2,47512
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)72.935, 77.482, 82.489
Angle α, β, γ (deg.)88.390, 64.244, 74.992
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,z

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Angiotensin-converting enzyme / ACE / Dipeptidyl carboxypeptidase I / Kininase II


Mass: 72606.508 Da / Num. of mol.: 2
Mutation: N9Q, N25Q, N82Q, N117Q, N131Q, N289Q, Q545R, P576L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACE, DCP, DCP1 / Production host: Cricetulus griseus (Chinese hamster)
References: UniProt: P12821, Hydrolases; Glycosylases; Glycosidases, i.e. enzymes that hydrolyse O- and S-glycosyl compounds, peptidyl-dipeptidase A

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Sugars , 3 types, 6 molecules

#2: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1- ...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


Type: oligosaccharide / Mass: 732.682 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1221m-1a_1-5]/1-1-2-3/a4-b1_a6-d1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}[(6+1)][a-L-Fucp]{}}}LINUCSPDB-CARE
#3: Polysaccharide alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 367.349 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
LFucpa1-6DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,2,1/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-2/a6-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(6+1)][a-L-Fucp]{}}}LINUCSPDB-CARE
#5: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 11 types, 815 molecules

#4: Chemical ChemComp-8J9 / (2~{S})-2-[[(2~{S})-1-[[(2~{S})-3-(4-hydroxyphenyl)-1-oxidanyl-1-oxidanylidene-propan-2-yl]amino]-1-oxidanylidene-hexan-2-yl]amino]-4-phenyl-butanoic acid


Mass: 456.531 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H32N2O6 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#7: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


Mass: 238.278 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#8: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#9: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#10: Chemical ChemComp-P33 / 3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL / HEPTAETHYLENE GLYCOL / PEG330


Mass: 326.383 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H30O8 / Comment: precipitant*YM
#11: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#12: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#13: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#14: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#15: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 793 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.78 Å3/Da / Density % sol: 55.75 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.1 M Tris/Bicine pH 8.5, 0.06 M Divalent cations, 30% PEG550MME/PEG20000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9159 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Dec 4, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9159 Å / Relative weight: 1
ReflectionResolution: 1.6→73.94 Å / Num. obs: 199691 / % possible obs: 96.7 % / Redundancy: 6.9 % / Biso Wilson estimate: 25.26 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.063 / Rpim(I) all: 0.026 / Net I/σ(I): 11.6
Reflection shellResolution: 1.6→1.63 Å / Redundancy: 6.5 % / Mean I/σ(I) obs: 1.7 / Num. unique obs: 9804 / CC1/2: 0.461 / % possible all: 95.4

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6F9V

6f9v


Resolution: 1.6→63.17 Å / SU ML: 0.1948 / Cross valid method: FREE R-VALUE / σ(F): 1.98 / Phase error: 25.6791
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2123 2000 1 %
Rwork0.188 197634 -
obs0.1882 199634 96.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 42.74 Å2
Refinement stepCycle: LAST / Resolution: 1.6→63.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9934 0 356 793 11083
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.009610757
X-RAY DIFFRACTIONf_angle_d0.880114630
X-RAY DIFFRACTIONf_chiral_restr0.05261533
X-RAY DIFFRACTIONf_plane_restr0.00811889
X-RAY DIFFRACTIONf_dihedral_angle_d14.99373950
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.640.36261200.336414046X-RAY DIFFRACTION95.37
1.64-1.680.30191520.311213967X-RAY DIFFRACTION95.75
1.68-1.730.31451490.285413911X-RAY DIFFRACTION95.51
1.73-1.790.27361330.266414004X-RAY DIFFRACTION95.88
1.79-1.850.2771520.253413938X-RAY DIFFRACTION95.85
1.85-1.930.29841560.252914018X-RAY DIFFRACTION96.08
1.93-2.020.29011320.23314099X-RAY DIFFRACTION96.44
2.02-2.120.24281340.219514089X-RAY DIFFRACTION96.49
2.12-2.260.23851460.207814166X-RAY DIFFRACTION97.09
2.26-2.430.22411570.199714237X-RAY DIFFRACTION97.3
2.43-2.670.21581350.189314236X-RAY DIFFRACTION97.73
2.67-3.060.20461520.18614280X-RAY DIFFRACTION97.84
3.06-3.860.18911410.163314291X-RAY DIFFRACTION98.07
3.86-63.170.15791410.143714352X-RAY DIFFRACTION98.32
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.424457170251.05658647804-0.3508238803340.824186409217-0.2732898715360.8995789409240.07080996728450.0305963184681-1.22174004155-0.17500503599-0.267104511963-0.04884580914360.21517470672-0.1244773121890.1671627087940.2090109127890.00435213786503-0.1598345133920.386295122607-0.06456527558870.906242306393-76.550368300652.6821343297-18.5470394532
22.0789602482-0.04293225643240.5263783325040.833557480690.09862345444630.992135938950.3390110874860.114281061403-0.407307908594-0.137146857772-0.1998661303710.1917056820460.03729496106810.0840441248862-0.06453521152830.214876013170.0286894587401-0.09346718491030.2411575466120.02045452876670.328121669317-65.717850780567.0327071275-18.9340936375
30.979770509917-0.325984601296-0.09827613194581.114973532980.2213194293870.5992276247530.08554214972030.133916300781-0.0500295117294-0.0788173326852-0.057575892255-0.0596491970319-0.01272726783550.0586784099297-0.02323533120280.173298989083-0.00519328788001-0.005567004352980.228272717980.02067562787090.16590405697-44.679368696263.7651996966-14.0290755105
42.281089425371.88892293151-0.7281190049873.84989388652-1.403636396450.493785703374-0.409832248233-0.364077501204-0.5505498208111.104916098860.3095636253060.04415847846690.635489361795-0.06792648046680.1138297160121.461079665010.3374790133570.1594500004050.6482672978540.1301518407560.521292281043-51.570960401876.63291410344.7467873592
50.623443608462-0.892101792967-0.235835996311.395721533770.4053630796341.81185840303-0.455186979556-0.53111993223-0.03968429973960.7567809590170.636842334478-0.2876847942780.7810674169960.5427475205590.2476119032450.8722196843450.305228442858-0.08048071496360.5296392044560.03612572624440.326090304994-44.171912219882.990437189330.5693590575
61.34875436357-1.00328502278-1.19948788722.396238291422.467235947993.45871425563-0.0812365802095-0.07898277431870.01761798529590.137662316971-0.02639942853160.1560268186890.0165068801673-0.155754893346.80340372134E-50.221723886211-0.03282304994660.006431168650870.1265852653020.04827720221640.204381561411-55.930478542796.990163696618.5302751305
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 1 through 43 )AA1 - 431 - 43
22chain 'A' and (resid 44 through 152 )AA44 - 15244 - 151
33chain 'A' and (resid 153 through 612 )AA153 - 612152 - 611
44chain 'B' and (resid 2 through 43 )BT2 - 431 - 42
55chain 'B' and (resid 44 through 152 )BT44 - 15243 - 148
66chain 'B' and (resid 153 through 610 )BT153 - 610149 - 606

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