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- PDB-7q27: Crystal structure of Angiotensin-1 converting enzyme C-domain in ... -

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Basic information

Entry
Database: PDB / ID: 7q27
TitleCrystal structure of Angiotensin-1 converting enzyme C-domain in complex with dual ACE/NEP inhibitor AD011
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 / positive regulation of peptidyl-cysteine S-nitrosylation ...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 / positive regulation of peptidyl-cysteine S-nitrosylation / negative regulation of calcium ion import / response to laminar fluid shear stress / negative regulation of gap junction assembly / metallodipeptidase activity / hormone catabolic process / bradykinin catabolic process / cellular response to aldosterone / angiogenesis involved in coronary vascular morphogenesis / response to thyroid hormone / negative regulation of D-glucose import / vasoconstriction / regulation of smooth muscle cell migration / regulation of hematopoietic stem cell proliferation / neutrophil mediated immunity / hormone metabolic process / 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 / arachidonate secretion / post-transcriptional regulation of gene expression / eating behavior / heterocyclic compound binding / peptide catabolic process / lung alveolus development / heart contraction / antigen processing and presentation of peptide antigen via MHC class I / positive regulation of systemic arterial blood pressure / response to dexamethasone / 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 / regulation of vasoconstriction / animal organ regeneration / peptidyl-dipeptidase activity / Metabolism of Angiotensinogen to Angiotensins / angiotensin maturation / metallocarboxypeptidase activity / positive regulation of vasoconstriction / sperm midpiece / blood vessel diameter maintenance / basal plasma membrane / kidney development / angiotensin-activated signaling pathway / female pregnancy / brush border membrane / response to nutrient levels / cellular response to glucose stimulus / 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 / response to hypoxia / lysosome / 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 / 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-8KC / ACETATE ION / BORIC ACID / IMIDAZOLE / Angiotensin-converting enzyme
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 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 1.3Nov 20, 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)71,29318
Polymers68,8621
Non-polymers2,43217
Water12,520695
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.454, 85.586, 134.052
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: E64G, 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 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.: 1
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: 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, 710 molecules

#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#7: Chemical ChemComp-8KC / (2~{S})-2-[[(2~{S})-1-[[(2~{S})-3-(1~{H}-indol-3-yl)-1-oxidanyl-1-oxidanylidene-propan-2-yl]amino]-1-oxidanylidene-hexan-2-yl]amino]-4-phenyl-butanoic acid


Mass: 479.568 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H33N3O5 / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#9: Chemical
ChemComp-BO3 / BORIC ACID


Mass: 61.833 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: BH3O3
#10: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


Mass: 238.278 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#11: Chemical ChemComp-IMD / IMIDAZOLE


Mass: 69.085 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H5N2
#12: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 695 / 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: 2.35 Å3/Da / Density % sol: 47.69 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 4 / Details: 0.1 M MIB pH 4.0, 5% glycerol, 16% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.9686 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 10, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9686 Å / Relative weight: 1
ReflectionResolution: 1.5→52.03 Å / Num. obs: 104713 / % possible obs: 100 % / Redundancy: 23.2 % / Biso Wilson estimate: 12.76 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.221 / Rpim(I) all: 0.047 / Net I/σ(I): 12
Reflection shellResolution: 1.5→1.53 Å / Redundancy: 22.9 % / Mean I/σ(I) obs: 2.7 / Num. unique obs: 5124 / CC1/2: 0.531 / % possible all: 99.8

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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: 1.5→47.13 Å / SU ML: 0.1509 / Cross valid method: FREE R-VALUE / σ(F): 1.45 / Phase error: 15.9223
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1781 2130 2.04 %
Rwork0.1485 102454 -
obs0.149 104584 99.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 19.68 Å2
Refinement stepCycle: LAST / Resolution: 1.5→47.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4778 0 158 695 5631
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01095298
X-RAY DIFFRACTIONf_angle_d1.04917222
X-RAY DIFFRACTIONf_chiral_restr0.0599761
X-RAY DIFFRACTIONf_plane_restr0.0118939
X-RAY DIFFRACTIONf_dihedral_angle_d14.82981966
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.530.31831470.26966733X-RAY DIFFRACTION100
1.53-1.570.27211380.24566731X-RAY DIFFRACTION100
1.57-1.620.22411560.21586763X-RAY DIFFRACTION100
1.62-1.660.24481410.1946736X-RAY DIFFRACTION100
1.66-1.720.17421510.18046775X-RAY DIFFRACTION99.99
1.72-1.780.20461250.16496764X-RAY DIFFRACTION100
1.78-1.850.19031430.16556777X-RAY DIFFRACTION100
1.85-1.930.19761200.14966831X-RAY DIFFRACTION100
1.93-2.040.17971460.14066797X-RAY DIFFRACTION100
2.04-2.160.15391370.12986815X-RAY DIFFRACTION100
2.16-2.330.16311580.12756822X-RAY DIFFRACTION100
2.33-2.560.1551550.12076860X-RAY DIFFRACTION100
2.56-2.940.1791260.1336886X-RAY DIFFRACTION100
2.94-3.70.16811220.13446969X-RAY DIFFRACTION100
3.7-47.130.14911650.13617195X-RAY DIFFRACTION99.88
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)
10.821826877314-0.754966245880.1711621872436.92654481593-1.626500981081.47534860355-0.0408075840460.1030135582460.0766077211285-0.0576540881175-0.0346980682148-0.184206172697-0.1924461611930.01961763453510.06088483843880.16989835428-0.0189218261434-0.01182894564960.158828153740.01739446900110.0669647764219-11.05461446867.015249053190.801420649048
21.262197360370.544971664495-0.1854254352611.66031264694-0.8107510272330.800152063093-0.09793765588120.1108257360780.10300648359-0.2240091175750.0393861865672-0.195440948687-0.1075678217610.04267388844970.05350172204340.157826373636-0.0133640454523-0.01810612269450.1543966300490.01318846119450.0796562398942-3.561594467037.945941269474.1878170543
30.8558020071190.872660426245-0.5237730482522.36928924734-1.36522667141.64056776145-0.07652906221060.0486477027897-0.152546468163-0.301369956613-0.00102849369348-0.1036785726030.2729052936470.04363165045080.1215705416580.1669011286070.00828313167521-0.005580724908980.110478893531-0.02113757505760.11842959349-3.15910208984-18.973238062317.8620320735
40.289461768230.0924451221246-0.2495952617570.721998729994-0.3492166329270.706078666012-0.0141887302935-0.00996742398994-0.01246842598580.03524970136070.01269620184040.007375316421240.01815624650820.01639479696240.00830124185830.0579897930494-0.00244964534606-0.01087001260410.0712995336726-0.002793698320350.057244447326-6.25326806049-9.7092543633733.069336768
51.349847608370.0181104694035-0.2933987669741.74655624367-0.3430738794221.41551390747-0.05466117098290.0847356279771-0.146725662127-0.1264249848630.02908234660040.07337957640690.175503167268-0.1436241631740.01873839841520.107356472712-0.0255407280499-0.01374334025190.118468800063-0.009160873310760.0916156385226-23.8530172389-11.086606956614.8938510736
61.535388924280.599016141677-0.4424891313042.08473507578-0.5383027428720.9815581494390.01498345362040.0287086436399-0.00959957206711-0.1299474410710.0002519157799630.155746996410.0172253426981-0.0811571118732-0.05220234194040.07015496657570.0136804862658-0.02092986312540.0814728333262-0.006655367595120.0806708939752-25.1776058633-2.2037429630923.2541412007
70.579272831704-0.0401766511310.06280067384290.535012408902-0.2000157209280.560249369373-0.0149556257971-0.0215615569520.01061988850980.0359599880330.0195474216210.0316587794487-0.00884320372255-0.01440304801340.002280570753560.0582588600637-0.002788002147140.003437777690350.05917939636-0.003387218187670.0562963377862-11.2561565374-3.7720193132230.7231266001
80.5519831409380.03754520401270.01844297354670.963847762147-0.6646778191211.638928572340.0202157639983-0.05898576001570.001111135195860.1650543878060.02422062088850.00413580765121-0.04996102787610.0541880353148-0.02643369317370.1110470828810.006482492663010.008412093638060.0964312997741-0.02331629535360.0889731033716-14.5792999997-0.74398513581640.9414439305
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 70 )40 - 701 - 31
22chain 'A' and (resid 71 through 128 )71 - 12832 - 89
33chain 'A' and (resid 129 through 174 )129 - 17490 - 135
44chain 'A' and (resid 175 through 300 )175 - 300136 - 261
55chain 'A' and (resid 301 through 393 )301 - 393262 - 354
66chain 'A' and (resid 394 through 439 )394 - 439355 - 400
77chain 'A' and (resid 440 through 568 )440 - 568401 - 529
88chain 'A' and (resid 569 through 625 )569 - 625530 - 586

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