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- PDB-7q28: Crystal structure of Angiotensin-1 converting enzyme C-domain in ... -

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Basic information

Entry
Database: PDB / ID: 7q28
TitleCrystal structure of Angiotensin-1 converting enzyme C-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 / 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 / metallodipeptidase activity / hormone catabolic process / bradykinin catabolic process / neutrophil mediated immunity / regulation of smooth muscle cell migration / regulation of hematopoietic stem cell proliferation / 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 / positive regulation of systemic arterial blood pressure / regulation of heart rate by cardiac conduction / regulation of systemic arterial blood pressure by renin-angiotensin / antigen processing and presentation of peptide antigen via MHC class I / 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 / metalloendopeptidase activity / regulation of synaptic plasticity / regulation of blood pressure / male gonad development / metallopeptidase activity / peptidase activity / actin binding / endopeptidase activity / spermatogenesis / 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-8J9 / BORIC ACID / DI(HYDROXYETHYL)ETHER / Angiotensin-converting enzyme
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 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 23, 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)70,98713
Polymers68,8621
Non-polymers2,12512
Water7,819434
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.254, 84.780, 133.376
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: E54G, 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 , 7 types, 444 molecules

#4: Chemical ChemComp-BO3 / BORIC ACID


Mass: 61.833 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: BH3O3
#5: 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.: 1 / Source method: obtained synthetically / Formula: C25H32N2O6 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#7: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


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


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


Mass: 18.015 Da / Num. of mol.: 434 / 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: 2.31 Å3/Da / Density % sol: 46.81 %
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: I03 / Wavelength: 0.9762 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 4, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 1.65→84.78 Å / Num. obs: 77571 / % possible obs: 100 % / Redundancy: 32.7 % / Biso Wilson estimate: 21.77 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.183 / Rpim(I) all: 0.032 / Net I/σ(I): 15.2
Reflection shellResolution: 1.65→1.68 Å / Redundancy: 22.1 % / Mean I/σ(I) obs: 1.2 / Num. unique obs: 3761 / CC1/2: 0.512 / % possible all: 99.7

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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: 1.65→71.55 Å / SU ML: 0.1694 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.3968
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1831 1800 2.33 %
Rwork0.1634 75376 -
obs0.1639 77176 99.57 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 28.93 Å2
Refinement stepCycle: LAST / Resolution: 1.65→71.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4706 0 137 434 5277
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00485062
X-RAY DIFFRACTIONf_angle_d0.82076880
X-RAY DIFFRACTIONf_chiral_restr0.0442735
X-RAY DIFFRACTIONf_plane_restr0.0081883
X-RAY DIFFRACTIONf_dihedral_angle_d14.63561873
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.65-1.690.27141300.26475748X-RAY DIFFRACTION99.56
1.69-1.740.27521410.23185703X-RAY DIFFRACTION99.95
1.74-1.80.22281390.20895688X-RAY DIFFRACTION98.95
1.8-1.870.24371350.20245721X-RAY DIFFRACTION99.09
1.87-1.940.24771300.20085751X-RAY DIFFRACTION99.31
1.94-2.030.24471350.17835733X-RAY DIFFRACTION99.21
2.03-2.140.21471520.16085704X-RAY DIFFRACTION99.39
2.14-2.270.18771630.1585767X-RAY DIFFRACTION99.56
2.27-2.440.18091170.15325806X-RAY DIFFRACTION99.81
2.44-2.690.16461280.15085828X-RAY DIFFRACTION99.68
2.69-3.080.17871430.15955870X-RAY DIFFRACTION99.93
3.08-3.880.16871370.15135901X-RAY DIFFRACTION100
3.88-71.550.14961500.15136156X-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)
11.602961702590.6278817307740.0004999549961031.24831821753-0.8410255201211.67584338837-0.1851107837170.145518087276-0.00638168712056-0.1529813222180.049336276826-0.099943522113-0.0767121512366-0.01977912422830.1316826807140.292216082411-0.01140999894760.007677533500580.3000961950250.004927490435050.173437673402-5.894454965917.118399532912.76478209386
20.9857896034350.69158813791-0.5590292525342.28801086327-1.393851083941.93046060515-0.1242358846710.0785002126455-0.166620571971-0.420393603496-0.00921203527344-0.1288779475070.4111489494240.04321454859270.1575164900590.2844487354430.01568059533170.02637535691370.212013672656-0.04024854998290.221591117239-2.93303473389-20.623004093120.8128087162
30.6306790670120.398299170332-0.6538315637051.47417984916-0.8709165188141.872689211010.00258418803294-0.003279569237820.01348590024120.09344502793170.007399770943180.0526638215335-0.02340995259810.0404025094989-0.008538622671930.1060139334080.00418101597578-0.01456127834060.151754933358-0.005819144236530.129422775927-6.75088913763-7.4730835402733.2686618057
41.772282383030.245971011697-0.7459147186782.08916953808-0.364818157881.77382343766-0.1599542201520.204595670676-0.218971256948-0.1949418797530.1250455190490.1089707063870.253434756917-0.2374777039940.02848251145860.182656318813-0.02631907723490.01243595171260.2188533253630.00749462822680.192976854528-24.3796623953-8.4987957221417.1863497622
50.848197306380.03988617394940.01027284656650.822065891194-0.3213436979541.00249309505-0.00630688792355-0.052282423362-0.01241199532520.07194697418750.02585631338740.0426092279116-0.0422291297471-0.00327287639551-0.00543546974080.1188260965450.001854479891070.01822214448720.1256807866890.0004084935819460.123526383061-10.1389106384-5.328702740931.5238831045
60.688918758432-0.2366928202010.3006674238651.40637531876-1.024863513862.05183488956-0.00726036912521-0.03291381456920.1198613218480.2007237048580.1506296148790.155541025269-0.309934881877-0.221965419864-0.1375913445120.1995435979230.03517277463520.05630333858480.172966689508-0.0007388362588230.193464817942-19.98250013743.2926935456235.872524104
Refinement TLS group

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

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 40 through 128 )40 - 1281 - 89
22chain 'A' and (resid 129 through 189 )129 - 18990 - 150
33chain 'A' and (resid 190 through 300 )190 - 300151 - 261
44chain 'A' and (resid 301 through 439 )301 - 439262 - 400
55chain 'A' and (resid 440 through 555 )440 - 555401 - 516
66chain 'A' and (resid 556 through 617 )556 - 617517 - 578

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