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- PDB-6suk: Crystal structure of Neprilysin in complex with Omapatrilat. -

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Basic information

Entry
Database: PDB / ID: 6suk
TitleCrystal structure of Neprilysin in complex with Omapatrilat.
ComponentsNeprilysin
KeywordsHYDROLASE / metallopeptidase / Neural endopeptidase / Omapatrilat
Function / homology
Function and homology information


neuropeptide processing / neprilysin / creatinine metabolic process / oligopeptidase activity / exopeptidase activity / substance P catabolic process / Physiological factors / cellular response to UV-A / peptide metabolic process / amyloid-beta clearance by cellular catabolic process ...neuropeptide processing / neprilysin / creatinine metabolic process / oligopeptidase activity / exopeptidase activity / substance P catabolic process / Physiological factors / cellular response to UV-A / peptide metabolic process / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / cardiolipin binding / neuron projection terminus / positive regulation of neurogenesis / cellular response to UV-B / phosphatidylserine binding / cellular response to cytokine stimulus / amyloid-beta clearance / brush border / replicative senescence / amyloid-beta metabolic process / Metabolism of Angiotensinogen to Angiotensins / angiotensin maturation / metallocarboxypeptidase activity / sensory perception of pain / peptide binding / secretory granule membrane / positive regulation of long-term synaptic potentiation / kidney development / placenta development / lung development / trans-Golgi network / protein catabolic process / protein processing / metalloendopeptidase activity / response to estrogen / synaptic vesicle / presynapse / cytoplasmic vesicle / endopeptidase activity / learning or memory / early endosome / ciliary basal body / membrane raft / axon / focal adhesion / neuronal cell body / synapse / centrosome / dendrite / Neutrophil degranulation / cell surface / protein homodimerization activity / proteolysis / extracellular exosome / zinc ion binding / nucleoplasm / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Neutral endopeptidase; domain 2 / Neutral endopeptidase , domain2 / Peptidase M13 / Peptidase M13, N-terminal domain / Peptidase M13, C-terminal domain / Peptidase M13, domain 2 / Peptidase family M13 / Peptidase family M13 / Neprilysin-like (M13) protease domain profile. / Collagenase (Catalytic Domain) ...Neutral endopeptidase; domain 2 / Neutral endopeptidase , domain2 / Peptidase M13 / Peptidase M13, N-terminal domain / Peptidase M13, C-terminal domain / Peptidase M13, domain 2 / Peptidase family M13 / Peptidase family M13 / Neprilysin-like (M13) protease domain profile. / Collagenase (Catalytic Domain) / Collagenase (Catalytic Domain) / Metallopeptidase, catalytic domain superfamily / Neutral zinc metallopeptidases, zinc-binding region signature. / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Omapatrilat / DI(HYDROXYETHYL)ETHER / Neprilysin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsCozier, G.E. / Acharya, K.R. / Sharma, U.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MR/M026647/1 United Kingdom
CitationJournal: J.Med.Chem. / Year: 2020
Title: Molecular Basis for Omapatrilat and Sampatrilat Binding to Neprilysin-Implications for Dual Inhibitor Design with Angiotensin-Converting Enzyme.
Authors: Sharma, U. / Cozier, G.E. / Sturrock, E.D. / Acharya, K.R.
History
DepositionSep 15, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 13, 2020Provider: repository / Type: Initial release
Revision 1.1May 20, 2020Group: Database references / Category: citation / citation_author / Item: _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jun 10, 2020Group: 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 1.3Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _entity.pdbx_description ..._chem_comp.name / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.4Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.5Oct 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: Neprilysin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,73813
Polymers79,9191
Non-polymers1,81912
Water9,962553
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: SAXS
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2330 Å2
ΔGint22 kcal/mol
Surface area29010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)107.935, 107.935, 112.841
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Space group name HallP322"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+2/3
#3: -x+y,-x,z+1/3
#4: x-y,-y,-z+1/3
#5: -x,-x+y,-z+2/3
#6: y,x,-z
Components on special symmetry positions
IDModelComponents
11A-1049-

HOH

21A-1446-

HOH

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Components

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Protein / Sugars , 2 types, 5 molecules A

#1: Protein Neprilysin / Atriopeptidase / Common acute lymphocytic leukemia antigen / CALLA / Enkephalinase / Neutral ...Atriopeptidase / Common acute lymphocytic leukemia antigen / CALLA / Enkephalinase / Neutral endopeptidase 24.11 / Neutral endopeptidase / Skin fibroblast elastase / SFE


Mass: 79918.859 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: N-terminal His-tag / Source: (gene. exp.) Homo sapiens (human) / Gene: MME, EPN / Production host: Komagataella pastoris (fungus) / Variant (production host): GS115 / References: UniProt: P08473, neprilysin
#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.: 4
Source method: isolated from a genetically manipulated source
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 , 5 types, 561 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-FT8 / Omapatrilat


Mass: 408.535 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H24N2O4S2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


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


Mass: 62.068 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: C2H6O2
#7: 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: 2.41 Å3/Da / Density % sol: 48.97 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 0.2 M NH4Cl, 22% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.92 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Apr 6, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 1.75→93.47 Å / Num. obs: 76891 / % possible obs: 100 % / Redundancy: 39.9 % / CC1/2: 1 / Rmerge(I) obs: 0.137 / Rpim(I) all: 0.022 / Net I/σ(I): 18.4
Reflection shellResolution: 1.75→1.78 Å / Redundancy: 34.1 % / Rmerge(I) obs: 4.105 / Mean I/σ(I) obs: 1.2 / Num. unique obs: 4166 / CC1/2: 0.507 / Rpim(I) all: 0.711 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
PHENIX1.13_2998refinement
DIALSv1-14-8data reduction
Aimlessdata scaling
PHASER2.8.2phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6GID

6gid


Resolution: 1.75→53.97 Å / SU ML: 0.2012 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 20.583 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflection
Rfree0.1997 2053 2.67 %
Rwork0.1655 74770 -
obs0.1664 76823 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 42.28 Å2
Refinement stepCycle: LAST / Resolution: 1.75→53.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5611 0 114 553 6278
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00325916
X-RAY DIFFRACTIONf_angle_d0.68338009
X-RAY DIFFRACTIONf_chiral_restr0.0407860
X-RAY DIFFRACTIONf_plane_restr0.00361046
X-RAY DIFFRACTIONf_dihedral_angle_d18.18543548
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.75-1.790.32671380.28424926X-RAY DIFFRACTION99.88
1.79-1.840.27851560.25494908X-RAY DIFFRACTION99.94
1.84-1.890.2551620.23184908X-RAY DIFFRACTION99.96
1.89-1.940.27511200.22154935X-RAY DIFFRACTION99.96
1.94-20.2281410.20554952X-RAY DIFFRACTION99.94
2-2.070.22011370.19014938X-RAY DIFFRACTION99.96
2.07-2.160.20681510.17524952X-RAY DIFFRACTION100
2.16-2.260.1921340.16874965X-RAY DIFFRACTION100
2.26-2.380.21321140.1694957X-RAY DIFFRACTION100
2.38-2.520.22391250.16734999X-RAY DIFFRACTION100
2.52-2.720.2041310.16934988X-RAY DIFFRACTION100
2.72-2.990.20191100.16735018X-RAY DIFFRACTION100
2.99-3.430.22291550.16675004X-RAY DIFFRACTION99.98
3.43-4.320.15781600.1395068X-RAY DIFFRACTION100
4.32-53.970.18481190.14975252X-RAY DIFFRACTION99.94
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)
11.162750529380.6203790847740.1098674456042.66072395528-0.6853821475381.197255190690.0543830930876-0.0570836548871-0.06370179168390.0347019766902-0.0340948005927-0.06354306625920.04310900796010.153092521764-0.02493322802690.191019863618-0.05918954963380.01572485798090.250398675894-0.01587547050370.13875078479527.2519652822-40.078867530528.779536479
21.80003969337-1.10291082651-1.227218060822.14101478411.468239732943.12972856743-0.03197535440890.131336335920.335119829005-0.4887808122640.1616554591070.0902970387046-0.5805640171080.230406007254-0.1745732770730.354058933186-0.1030655227-0.0373236718090.25082546290.03566036823170.32857387381714.1577680806-19.30454342734.09028686556
30.9192915742370.1978492565050.3362602769873.86595285441.288012978982.856297045120.0706197401107-0.012507907390.06563903285490.115597633473-0.06180712384160.332847491356-0.00307461267159-0.310625678555-0.03321825292620.1874182067730.00604739728991-0.0131055898610.2641584735880.02838394884720.351826424093.70324714337-26.576956639720.2354892503
41.57972875347-0.266405595258-0.1998240943151.948715420661.322915893482.33442793124-0.0737061314430.2902759449670.233399350607-0.3249009571720.04669572928950.21905554784-0.288516691282-0.008885705159130.02233098202870.309467586566-0.0514772154949-0.0751416384660.2452773754250.0911350620550.3492563048697.63712353619-23.25008421893.28354782881
50.9409821366470.3029016444610.2019466897921.030865691830.1456755418820.8342118543210.02099181936330.151764364644-0.0127684998301-0.1484006460130.0301292418344-0.13370876877-0.02271189830470.271067649992-0.08468492074620.220364226398-0.01570540153830.02006697462310.2885200537760.02673569575790.17591088105630.7489999025-40.080823834214.0726920218
60.4190421281480.1564826245470.422982510790.603125782922-0.2456994209470.818275039729-0.0398012289080.2133089430330.110187623601-0.3120743990120.0862149810016-0.0876163999421-0.04866402749790.300214607475-0.05617409515060.330926992266-0.06463219345960.02156097526080.375747524950.007615651688550.25887429664929.732992718-33.02129641117.82301156426
71.015873207930.1161180424050.2922279243381.011357200590.1264586338251.895670885740.1448954465430.102111661407-0.32151757705-0.0894118828483-0.05164933175650.05050659507120.352055212547-0.0237010498534-0.07324760640190.260687723162-0.0190715791819-0.03544776407670.171970310748-0.04520456281010.25711343355419.9415623097-58.245426215514.3462560859
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 53 through 163 )
2X-RAY DIFFRACTION2chain 'A' and (resid 164 through 219 )
3X-RAY DIFFRACTION3chain 'A' and (resid 220 through 258 )
4X-RAY DIFFRACTION4chain 'A' and (resid 259 through 381 )
5X-RAY DIFFRACTION5chain 'A' and (resid 382 through 505 )
6X-RAY DIFFRACTION6chain 'A' and (resid 506 through 558 )
7X-RAY DIFFRACTION7chain 'A' and (resid 559 through 749 )

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