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- PDB-7q29: Crystal structure of Angiotensin-1 converting enzyme C-domain in ... -

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Basic information

Entry
Database: PDB / ID: 7q29
TitleCrystal structure of Angiotensin-1 converting enzyme C-domain in complex with dual ACE/NEP inhibitor AD013
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 / exopeptidase activity / regulation of angiotensin metabolic process / substance P catabolic process / tripeptidyl-peptidase activity / peptidyl-dipeptidase A / regulation of renal output by angiotensin / negative regulation of gap junction assembly ...mononuclear cell proliferation / cell proliferation in bone marrow / bradykinin receptor binding / exopeptidase activity / regulation of angiotensin metabolic process / substance P catabolic process / tripeptidyl-peptidase activity / peptidyl-dipeptidase A / regulation of renal output by angiotensin / negative regulation of gap junction assembly / hormone catabolic process / bradykinin catabolic process / metallodipeptidase activity / regulation of smooth muscle cell migration / regulation of hematopoietic stem cell proliferation / neutrophil mediated immunity / hormone metabolic process / mitogen-activated protein kinase binding / mitogen-activated protein kinase kinase binding / chloride ion binding / arachidonate secretion / post-transcriptional regulation of gene expression / peptide catabolic process / heart contraction / antigen processing and presentation of peptide antigen via MHC class I / positive regulation of systemic arterial blood pressure / regulation of heart rate by cardiac conduction / regulation of systemic arterial blood pressure by renin-angiotensin / blood vessel remodeling / amyloid-beta metabolic process / hematopoietic stem cell differentiation / peptidyl-dipeptidase activity / regulation of vasoconstriction / Metabolism of Angiotensinogen to Angiotensins / angiotensin maturation / metallocarboxypeptidase activity / blood vessel diameter maintenance / angiotensin-activated signaling pathway / kidney development / regulation of synaptic plasticity / metalloendopeptidase activity / regulation of blood pressure / male gonad development / metallopeptidase activity / peptidase activity / actin binding / spermatogenesis / endopeptidase activity / calmodulin binding / lysosome / endosome / negative regulation of gene expression / external side of plasma membrane / proteolysis / extracellular space / extracellular exosome / extracellular region / zinc ion binding / 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-8JV / BORIC ACID / IMIDAZOLE / 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
Revision 1.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Angiotensin-converting enzyme
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,38517
Polymers68,8621
Non-polymers2,52416
Water9,962553
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.164, 84.765, 132.728
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 68861.875 Da / Num. of mol.: 1 / Mutation: E46G, N90Q, N155Q, N337Q, N586Q
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 , 2 types, 2 molecules

#2: Polysaccharide alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-3)-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: 894.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/4,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5][a1221m-1a_1-5]/1-1-2-3-4/a4-b1_a6-e1_b4-c1_c3-d1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}[(6+1)][a-L-Fucp]{}}}LINUCSPDB-CARE
#3: 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.: 1 / 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 , 9 types, 567 molecules

#4: Chemical
ChemComp-BO3 / BORIC ACID


Mass: 61.833 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: BH3O3
#5: Chemical ChemComp-IMD / IMIDAZOLE


Mass: 69.085 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H5N2
#6: Chemical ChemComp-8JV / (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


Mass: 424.490 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H28N2O5 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#8: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


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


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#10: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#11: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#12: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 553 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.29 Å3/Da / Density % sol: 46.38 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 4 / Details: 0.1 M MIB pH 4.0, 5% glycerol, 15% PEG 3350

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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: Feb 4, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9159 Å / Relative weight: 1
ReflectionResolution: 1.6→66.36 Å / Num. obs: 84046 / % possible obs: 99.6 % / Redundancy: 23.9 % / Biso Wilson estimate: 14.82 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.213 / Rpim(I) all: 0.044 / Net I/σ(I): 11.1
Reflection shellResolution: 1.6→1.63 Å / Redundancy: 17.4 % / Mean I/σ(I) obs: 2.4 / Num. unique obs: 3962 / CC1/2: 0.413 / % possible all: 96.8

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6F9T

6f9t


Resolution: 1.6→66.36 Å / SU ML: 0.167 / Cross valid method: FREE R-VALUE / σ(F): 1.43 / Phase error: 17.6492
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1843 2013 2.4 %
Rwork0.1605 81951 -
obs0.161 83964 99.57 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21.33 Å2
Refinement stepCycle: LAST / Resolution: 1.6→66.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4706 0 164 553 5423
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00395092
X-RAY DIFFRACTIONf_angle_d0.75646917
X-RAY DIFFRACTIONf_chiral_restr0.042736
X-RAY DIFFRACTIONf_plane_restr0.0066886
X-RAY DIFFRACTIONf_dihedral_angle_d14.45991881
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.640.29591490.29045620X-RAY DIFFRACTION96.76
1.64-1.680.3141450.27455680X-RAY DIFFRACTION98.48
1.68-1.730.24831320.24375795X-RAY DIFFRACTION99.46
1.73-1.790.24031460.21985787X-RAY DIFFRACTION99.78
1.79-1.850.28061180.20435845X-RAY DIFFRACTION99.73
1.85-1.930.21861350.18535832X-RAY DIFFRACTION99.82
1.93-2.020.2051310.15585841X-RAY DIFFRACTION99.97
2.02-2.120.19551400.1445846X-RAY DIFFRACTION99.93
2.12-2.260.1531430.13925861X-RAY DIFFRACTION100
2.26-2.430.17631590.13435858X-RAY DIFFRACTION100
2.43-2.670.14891560.13345884X-RAY DIFFRACTION99.98
2.67-3.060.18071620.14795892X-RAY DIFFRACTION100
3.06-3.860.1551420.13915991X-RAY DIFFRACTION100
3.86-66.360.15561550.14586219X-RAY DIFFRACTION99.95
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)
11.06002808785-0.5528292753890.2537701426945.82256318486-2.229231525251.89314235879-0.04623633240850.1465702289590.056393747338-0.0859467292241-0.0777828204558-0.153896229564-0.1670219092030.004733851042930.1239790286310.195744552634-0.0188694093967-0.007706407264120.2163102799830.01294160052560.0871495109942-10.68314447056.715278160920.651155179732
21.642904166740.670755316737-0.03356023569681.47407322312-1.089663385171.21184860407-0.1885582228490.1175305364050.0937543663878-0.1307062438660.0982969367406-0.179716350545-0.1568828062690.03074803131990.09676010125730.203709544539-0.0118632832087-0.01184247515790.2012275644440.01338454141480.0932218830497-3.296605051277.445344137033.95447381446
30.8363531701790.560823705101-0.3524129729492.16886251717-0.6183347834421.18519921268-0.1335310062650.103872188837-0.18999842664-0.3336803649250.0215717830655-0.1248893761210.3220124135550.02229707751190.1615282029250.1732715978390.01242862637050.00105971360210.133202678792-0.02338248282050.13889071003-3.31102968283-19.22748288717.6883112761
40.3189717138980.058433358776-0.1174475919350.459592721309-0.2877823564710.643276608379-0.0139310517180.0293226199822-0.0383149183842-0.02519310557320.01570611122040.01034225995050.0451282120766-0.0230196648277-0.006805623776720.101452773724-0.002675007824030.01187016586610.0917103468674-0.01020082317210.104198917319-12.0210358749-10.874756745627.0426687051
51.456094106450.22016187194-0.4395116963711.6528736825-0.06882648695211.1717361779-0.02699663977940.0959116330571-0.030540860222-0.1163881253160.04432349222110.1228162412150.0605565683038-0.0928899532721-0.02524627973580.07656898041490.00124282817878-0.01487559950380.09292859513610.005379265645910.0892972998489-23.599983834-4.6877893653419.3999154207
60.6422025557350.110122490138-0.06315988631640.767022853966-0.2148946603760.8007756120940.000706438700037-0.00626819710869-0.02596903152740.0435758234372-0.0079944400779-0.0181575221529-0.003957583289550.04777782036860.0129240645640.0681995700069-0.0007973688128930.008568942713170.0695227005389-0.007012262140610.070414095366-6.92022229522-5.9706469170431.4366695142
71.952069055010.305017996246-0.05047628312061.165932548640.04474755515141.46793972303-0.002108888226920.04845947156630.1542500393710.03063333928410.07948544842110.198703964748-0.132934930069-0.187097825038-0.09527693272590.1141911810650.04820844627120.02290570924530.1149902282590.03619525835150.161135283128-26.65089777118.2329822416826.5044252493
80.5900200199510.124267761826-0.08207729640180.666119730405-0.336359096931.483302468070.0131630647929-0.01594541763090.01933030453910.1220420117040.08413147388650.112385266567-0.144034699233-0.118973891252-0.03908472327490.1381808028290.007350066856630.02020852697510.109725847747-0.02450243592670.127398936591-18.1294186919-1.4325562099138.2390016943
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A

IDRefine TLS-IDSelection detailsLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 40 through 70 )A40 - 701 - 31
22chain 'A' and (resid 71 through 128 )A71 - 12832 - 89
33chain 'A' and (resid 129 through 174 )A129 - 17490 - 135
44chain 'A' and (resid 175 through 358 )A175 - 358136 - 319
55chain 'A' and (resid 359 through 439 )A359 - 439320 - 400
66chain 'A' and (resid 440 through 540 )A440 - 540401 - 501
77chain 'A' and (resid 541 through 589 )A541 - 589502 - 550
88chain 'A' and (resid 590 through 617 )A - J590 - 803551

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