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- PDB-6thp: Neprilysin in complex with the inhibitor (R)-4-(1-carboxy-3-(3'-c... -

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Basic information

Entry
Database: PDB / ID: 6thp
TitleNeprilysin in complex with the inhibitor (R)-4-(1-carboxy-3-(3'-chlorobiphenyl-4-yl)propan-2-ylamino)-4-oxobutanoic acid
ComponentsNeprilysin
KeywordsHYDROLASE / Inhibitor / Complex
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 / cellular response to UV-B / phosphatidylserine binding / amyloid-beta clearance / 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 / placenta development / peptide binding / lung development / protein catabolic process / trans-Golgi network / protein processing / metalloendopeptidase activity / response to estrogen / synaptic vesicle / presynapse / cytoplasmic vesicle / endopeptidase activity / early endosome / learning or memory / membrane raft / axon / focal adhesion / neuronal cell body / synapse / dendrite / Neutrophil degranulation / cell surface / protein homodimerization activity / proteolysis / extracellular exosome / zinc ion binding / 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
Chem-N9Q / Neprilysin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.54 Å
AuthorsSchiering, N. / Wiesmann, C.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Structure-Guided Design of Substituted Biphenyl Butanoic Acid Derivatives as Neprilysin Inhibitors.
Authors: Kawanami, T. / Karki, R.G. / Cody, E. / Liu, Q. / Liang, G. / Ksander, G.M. / Rigel, D.F. / Schiering, N. / Gong, Y. / Coppola, G.M. / Iwaki, Y. / Sun, R. / Neubert, A. / Fan, L. / Ingles, S. ...Authors: Kawanami, T. / Karki, R.G. / Cody, E. / Liu, Q. / Liang, G. / Ksander, G.M. / Rigel, D.F. / Schiering, N. / Gong, Y. / Coppola, G.M. / Iwaki, Y. / Sun, R. / Neubert, A. / Fan, L. / Ingles, S. / D'Arcy, A. / Villard, F. / Ramage, P. / Jeng, A.Y. / Leung-Chu, J. / Liu, J. / Beil, M. / Fu, F. / Chen, W. / Cumin, F. / Wiesmann, C. / Mogi, M.
History
DepositionNov 21, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 12, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
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 / 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_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_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

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Assembly

Deposited unit
A: Neprilysin
B: Neprilysin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)161,73114
Polymers159,0512
Non-polymers2,68012
Water6,341352
1
A: Neprilysin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)80,8667
Polymers79,5261
Non-polymers1,3406
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Neprilysin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)80,8667
Polymers79,5261
Non-polymers1,3406
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)59.790, 109.390, 248.018
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12L
22M

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1114A54 - 749
2114B54 - 749
1121L1
2121M1

NCS ensembles :
ID
1
2

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Components

#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: 79525.508 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P08473, neprilysin
#2: 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.: 8
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
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-N9Q / 4-[[(2~{R})-1-[4-(3-chlorophenyl)phenyl]-4-oxidanyl-4-oxidanylidene-butan-2-yl]amino]-4-oxidanylidene-butanoic acid


Mass: 389.830 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H20ClNO5 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 352 / Source method: isolated from a natural source / Formula: H2O
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: 2.55 Å3/Da / Density % sol: 51.76 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1 M Bis-Tris pH 6.5, 25% W/V PEG 3350, 2 mM MGCL2, 0.2 M Ammoniumacetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CMOS / Date: Jun 22, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.54→82.68 Å / Num. obs: 54635 / % possible obs: 99.8 % / Redundancy: 5.49 % / Rmerge(I) obs: 0.114 / Net I/σ(I): 14.47
Reflection shellResolution: 2.54→2.62 Å / Redundancy: 5.59 % / Rmerge(I) obs: 0.536 / Mean I/σ(I) obs: 3.91 / Num. unique obs: 4796 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.5.0063refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5JMY

5jmy


Resolution: 2.54→65.94 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.887 / SU B: 11.337 / SU ML: 0.241 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.807 / ESU R Free: 0.324
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2639 2732 5 %RANDOM
Rwork0.2051 ---
obs0.2081 51899 99.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 69.24 Å2 / Biso mean: 40.631 Å2 / Biso min: 15 Å2
Baniso -1Baniso -2Baniso -3
1--0.23 Å20 Å20 Å2
2--0.82 Å20 Å2
3----0.58 Å2
Refinement stepCycle: final / Resolution: 2.54→65.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11190 0 168 352 11710
Biso mean--44.28 34.05 -
Num. residues----1392
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.02211614
X-RAY DIFFRACTIONr_angle_refined_deg1.3381.96115724
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.76151390
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.19425.051586
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.137152016
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.5191562
X-RAY DIFFRACTIONr_chiral_restr0.0940.21688
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0218916
Refine LS restraints NCS

Dom-ID: 1 / Refine-ID: X-RAY DIFFRACTION

Ens-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
1A5595MEDIUM POSITIONAL0.310.5
1A5595MEDIUM THERMAL0.892
2B27TIGHT POSITIONAL0.030.05
2B27TIGHT THERMAL0.170.5
LS refinement shellResolution: 2.54→2.606 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.322 201 -
Rwork0.246 3822 -
all-4023 -
obs--99.9 %

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