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- PDB-6xvp: Crystal structure of Neprilysin in complex with Sampatrilat. -

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Basic information

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


neuropeptide processing / neprilysin / creatinine metabolic process / oligopeptidase activity / exopeptidase activity / substance P catabolic process / Physiological factors / peptide metabolic process / cellular response to UV-A / amyloid-beta clearance by cellular catabolic process ...neuropeptide processing / neprilysin / creatinine metabolic process / oligopeptidase activity / exopeptidase activity / substance P catabolic process / Physiological factors / peptide metabolic process / cellular response to UV-A / amyloid-beta clearance by cellular catabolic process / cardiolipin binding / hormone catabolic process / bradykinin catabolic process / neuron projection terminus / positive regulation of neurogenesis / cellular response to UV-B / amyloid-beta clearance / phosphatidylserine binding / cellular response to cytokine stimulus / brush border / replicative senescence / amyloid-beta metabolic process / Metabolism of Angiotensinogen to Angiotensins / sensory perception of pain / secretory granule membrane / kidney development / positive regulation of long-term synaptic potentiation / peptide binding / lung development / protein catabolic process / placenta development / trans-Golgi network / protein processing / metalloendopeptidase activity / response to estrogen / synaptic vesicle / presynapse / cytoplasmic vesicle / endopeptidase activity / learning or memory / early endosome / membrane raft / axon / focal adhesion / neuronal cell body / synapse / dendrite / Neutrophil degranulation / cell surface / protein homodimerization activity / proteolysis / zinc ion binding / extracellular exosome / membrane / plasma membrane / cytoplasm
Similarity search - Function
Neutral endopeptidase; domain 2 / Neutral endopeptidase , domain2 / Neprilysin-like (M13) protease domain profile. / Peptidase M13 / Peptidase M13, N-terminal domain / Peptidase M13, C-terminal domain / Peptidase M13, domain 2 / Peptidase family M13 / Peptidase family M13 / Collagenase (Catalytic Domain) ...Neutral endopeptidase; domain 2 / Neutral endopeptidase , domain2 / Neprilysin-like (M13) protease domain profile. / Peptidase M13 / Peptidase M13, N-terminal domain / Peptidase M13, C-terminal domain / Peptidase M13, domain 2 / Peptidase family M13 / Peptidase family M13 / 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
Sampatrilat / Neprilysin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.65 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
DepositionJan 22, 2020Deposition 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

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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)81,64010
Polymers79,9191
Non-polymers1,7219
Water70339
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1620 Å2
ΔGint21 kcal/mol
Surface area28850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)108.089, 108.089, 112.826
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

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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
Source: (gene. exp.) Homo sapiens (human) / Gene: MME, EPN / Cell line (production host): GS115 / Production host: Komagataella pastoris (fungus) / References: UniProt: P08473, neprilysin
#4: 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 , 4 types, 44 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-D0Z / Sampatrilat


Mass: 584.682 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H40N4O9S / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 39 / 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: 2.38 Å3/Da / Density % sol: 48.33 %
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: 2.65→93.61 Å / Num. obs: 22602 / % possible obs: 100 % / Redundancy: 37.1 % / Biso Wilson estimate: 52.96 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.472 / Rpim(I) all: 0.078 / Net I/σ(I): 7.8
Reflection shellResolution: 2.65→2.78 Å / Redundancy: 26.9 % / Rmerge(I) obs: 4.442 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 2959 / CC1/2: 0.535 / Rpim(I) all: 0.865 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
PHENIX1.13_2998refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6GID

6gid


Resolution: 2.65→72.04 Å / SU ML: 0.382 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.8051
RfactorNum. reflection% reflection
Rfree0.2373 1196 5.31 %
Rwork0.191 --
obs0.1935 22542 99.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 61.47 Å2
Refinement stepCycle: LAST / Resolution: 2.65→72.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5595 0 109 39 5743
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00295838
X-RAY DIFFRACTIONf_angle_d0.54037906
X-RAY DIFFRACTIONf_chiral_restr0.0375852
X-RAY DIFFRACTIONf_plane_restr0.0031027
X-RAY DIFFRACTIONf_dihedral_angle_d18.56093505
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.65-2.760.35871430.30272299X-RAY DIFFRACTION99.92
2.76-2.880.3091270.27762341X-RAY DIFFRACTION99.72
2.88-3.030.34071180.27172354X-RAY DIFFRACTION99.92
3.03-3.220.34551380.24762352X-RAY DIFFRACTION99.76
3.22-3.470.27161440.22752350X-RAY DIFFRACTION99.84
3.47-3.820.26461390.19632345X-RAY DIFFRACTION99.88
3.82-4.380.20561350.15312379X-RAY DIFFRACTION99.96
4.38-5.510.17731090.14762415X-RAY DIFFRACTION99.92
5.51-72.040.1791430.15592511X-RAY DIFFRACTION99.81
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)
10.7168820639320.0196194382691-0.2943085874151.201658076050.3737530859070.6714413825430.053828950392-0.03525493937860.0350324770630.0788900314172-0.0212761748792-0.00494288805603-0.0252536587143-0.0175568192153-0.02675653674230.359113090408-0.040574844944-0.02692124912060.401998847673-0.004901283200890.303523980714-27.348023770240.093152425428.8074778943
21.11777581744-0.00504813179694-0.1932008369521.09263727391-0.2204435383941.07240523612-0.0254311053030.213043662382-0.181871256493-0.1724617444640.00405260113931-0.2361017326570.1047781522750.07759480274660.01539162299960.3585617665430.0129011391050.05283413006530.431410432233-0.05765985736460.443254623069-8.9075400068623.1046549758.29297531247
30.9431830857470.335736259931-0.4123195716691.41935935443-0.4814324366090.653160563191-0.01913617544140.283946667163-0.00677781707251-0.1688511235840.03199761375780.1621150623650.101041338685-0.1274324358740.02193110456690.337876621694-0.0188052370465-0.04107460076810.439519724116-0.02525203919360.279120099206-32.673533389238.856916954311.3511713001
41.169677318990.0677977817704-0.4710889316881.03532466635-0.340244138771.408540232820.08253743123640.1539954259550.225186086007-0.095607873853-0.0609344862918-0.0355958133309-0.177998181380.0542437421919-0.03140765600710.347567615599-0.01892754193030.02556733734740.3737953898180.06896603907470.359555880287-21.418555389256.119134825213.278754327
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 54 through 163 )
2X-RAY DIFFRACTION2chain 'A' and (resid 164 through 398 )
3X-RAY DIFFRACTION3chain 'A' and (resid 399 through 526 )
4X-RAY DIFFRACTION4chain 'A' and (resid 527 through 749 )

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