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- PDB-6sh2: Crystal structure of human neprilysin E584D in complex with C-typ... -

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Basic information

Entry
Database: PDB / ID: 6sh2
TitleCrystal structure of human neprilysin E584D in complex with C-type natriuretic peptide.
Components
  • C-type natriuretic peptide fragment (CNP)
  • Neprilysin
KeywordsPEPTIDE BINDING PROTEIN / Zinc Metalloprotease / Neprilysin / Neutral Endopeptidase.
Function / homology
Function and homology information


neuropeptide processing / neprilysin / creatinine metabolic process / oligopeptidase activity / exopeptidase activity / Physiological factors / substance P catabolic process / 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 / Physiological factors / substance P catabolic process / 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 / phosphatidylserine binding / cellular response to UV-B / amyloid-beta clearance / cellular response to cytokine stimulus / brush border / replicative senescence / Metabolism of Angiotensinogen to Angiotensins / amyloid-beta metabolic process / sensory perception of pain / kidney development / secretory granule membrane / placenta development / positive regulation of long-term synaptic potentiation / peptide binding / lung development / protein catabolic process / trans-Golgi network / metalloendopeptidase activity / protein processing / response to estrogen / synaptic vesicle / presynapse / cytoplasmic vesicle / endopeptidase activity / learning or memory / early endosome / membrane raft / axon / focal adhesion / neuronal cell body / dendrite / synapse / Neutrophil degranulation / cell surface / protein homodimerization activity / proteolysis / extracellular exosome / zinc ion binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
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 / Metallopeptidase, catalytic domain superfamily / Neutral zinc metallopeptidases, zinc-binding region signature.
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsMoss, S. / Subramanian, V. / Acharya, K.R.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Other private286 (AS-PhD2015b006) United Kingdom
CitationJournal: Febs Lett. / Year: 2020
Title: Crystal structure of peptide-bound neprilysin reveals key binding interactions.
Authors: Moss, S. / Subramanian, V. / Acharya, K.R.
History
DepositionAug 5, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 25, 2019Provider: repository / Type: Initial release
Revision 1.1Feb 5, 2020Group: Data collection / Database references / Category: chem_comp / citation
Item: _chem_comp.type / _citation.journal_volume ..._chem_comp.type / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.2Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn
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 1.3Jan 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
AAA: Neprilysin
DDD: C-type natriuretic peptide fragment (CNP)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)80,8359
Polymers79,8142
Non-polymers1,0217
Water181
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2070 Å2
ΔGint-54 kcal/mol
Surface area28320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.267, 109.267, 112.579
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221

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Components

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Protein / Protein/peptide / Sugars , 3 types, 6 molecules AAADDD

#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: 79511.477 Da / Num. of mol.: 1 / Mutation: E584D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MME, EPN / Production host: Komagataella phaffii GS115 (fungus) / References: UniProt: P08473, neprilysin
#2: Protein/peptide C-type natriuretic peptide fragment (CNP)


Mass: 302.326 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#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 / N-Acetylglucosamine


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 , 3 types, 4 molecules

#4: Chemical ChemComp-ZN / ZINC ION


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


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


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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: 2.43 Å3/Da / Density % sol: 49.4 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion / Details: Potassium nitrate, Sodium iodide, 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 EIGER2 X 16M / Detector: PIXEL / Date: May 13, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 2.6→72.44 Å / Num. obs: 24386 / % possible obs: 100 % / Redundancy: 39.9 % / CC1/2: 1 / Net I/σ(I): 17.3
Reflection shellResolution: 2.6→2.72 Å / Num. unique obs: 2945 / CC1/2: 0.604

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Processing

Software
NameVersionClassification
REFMAC5.8.0253refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6GID
Resolution: 2.6→72.44 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.886 / SU B: 20.668 / SU ML: 0.407 / Cross valid method: FREE R-VALUE / ESU R: 1.576 / ESU R Free: 0.372
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2866 1287 5.285 %
Rwork0.2435 --
all0.246 --
obs-24353 99.975 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 91.557 Å2
Baniso -1Baniso -2Baniso -3
1-1.816 Å20.908 Å2-0 Å2
2--1.816 Å20 Å2
3----5.892 Å2
Refinement stepCycle: LAST / Resolution: 2.6→72.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5475 0 59 1 5535
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0135658
X-RAY DIFFRACTIONr_bond_other_d0.0020.0174958
X-RAY DIFFRACTIONr_angle_refined_deg1.1481.6527700
X-RAY DIFFRACTIONr_angle_other_deg1.1141.58611497
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8525698
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.30323.689309
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.35915898
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.3971528
X-RAY DIFFRACTIONr_chiral_restr0.0310.2750
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.026458
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021194
X-RAY DIFFRACTIONr_nbd_refined0.1570.21154
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1620.24550
X-RAY DIFFRACTIONr_nbtor_refined0.1510.22749
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0810.22157
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.10.2135
X-RAY DIFFRACTIONr_metal_ion_refined0.0840.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.0570.24
X-RAY DIFFRACTIONr_nbd_other0.1340.219
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.0570.22
X-RAY DIFFRACTIONr_mcbond_it1.69810.1152797
X-RAY DIFFRACTIONr_mcbond_other1.69710.1162797
X-RAY DIFFRACTIONr_mcangle_it2.93115.1753493
X-RAY DIFFRACTIONr_mcangle_other2.93115.1753494
X-RAY DIFFRACTIONr_scbond_it1.41810.2182860
X-RAY DIFFRACTIONr_scbond_other1.41810.2182861
X-RAY DIFFRACTIONr_scangle_it2.56715.2914207
X-RAY DIFFRACTIONr_scangle_other2.56715.2914208
X-RAY DIFFRACTIONr_lrange_it4.753117.9246304
X-RAY DIFFRACTIONr_lrange_other4.752117.9296305
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.6-2.6680.401880.40316890.40317770.5830.5981000.403
2.668-2.7410.43770.38816420.3917190.6320.641000.388
2.741-2.820.41830.36916180.37117010.6410.6621000.363
2.82-2.9070.35790.34915500.34916300.7370.75799.93870.339
2.907-3.0020.45760.35615110.36115870.6790.6931000.341
3.002-3.1070.384760.3514610.35215380.7850.75299.9350.331
3.107-3.2240.345850.31613990.31814840.8030.8161000.298
3.224-3.3560.431570.31513650.31914230.7530.81999.92970.295
3.356-3.5050.363730.30513100.30813830.7880.8461000.284
3.505-3.6760.313790.28412280.28513070.8770.8821000.27
3.676-3.8740.285630.23912060.24112690.8980.9171000.228
3.874-4.1090.277610.23511270.23711880.8970.9151000.226
4.109-4.3920.243650.21910640.2211290.9170.9251000.214
4.392-4.7430.252640.1919930.19510570.9250.9481000.192
4.743-5.1940.249540.1968990.1989530.9250.9481000.198
5.194-5.8050.315570.2288340.2348910.8830.9181000.23
5.805-6.6990.216450.227410.227860.9420.941000.227
6.699-8.1940.272450.1996340.2046790.9180.9351000.21
8.194-11.5450.154330.1524960.1535290.9720.9711000.168
11.545-94.6280.346270.262990.2663290.8350.93799.08810.289

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