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- PDB-2qpj: Human NEP complexed with a bifunctional NEP/DPP IV inhibitor -

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Basic information

Entry
Database: PDB / ID: 2qpj
TitleHuman NEP complexed with a bifunctional NEP/DPP IV inhibitor
ComponentsNeprilysin
KeywordsHYDROLASE / zinc-dependent metalloprotease / Glycoprotein / Membrane / Metal-binding / Signal-anchor / Transmembrane / LT3_9
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 / 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
Chem-I20 / Neprilysin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsOefner, C. / Dale, G.E.
CitationJournal: Acta Crystallogr.,Sect.D / Year: 2007
Title: Structural studies of a bifunctional inhibitor of neprilysin and DPP-IV.
Authors: Oefner, C. / Pierau, S. / Schulz, H. / Dale, G.E.
History
DepositionJul 24, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2007Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.2Jul 29, 2020Group: Advisory / Data collection ...Advisory / Data collection / Derived calculations / Structure summary
Category: chem_comp / database_PDB_caveat ...chem_comp / database_PDB_caveat / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _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_asym_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 / _struct_conn.ptnr2_label_seq_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.3Aug 30, 2023Group: 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)80,8046
Polymers79,5261
Non-polymers1,2795
Water5,242291
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)107.123, 107.123, 112.375
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein Neprilysin / Neutral endopeptidase / NEP / Enkephalinase / Neutral endopeptidase 24.11 / Atriopeptidase / Common ...Neutral endopeptidase / NEP / Enkephalinase / Neutral endopeptidase 24.11 / Atriopeptidase / Common acute lymphocytic leukemia antigen / CALLA / CD10 antigen


Mass: 79525.508 Da / Num. of mol.: 1 / Fragment: EXTRACELLULAR DOMAIN; UNP residues 55-750
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MME, EPN / Production host: Saccharomyces cerevisiae (brewer's yeast) / 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


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3
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.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-I20 / (2S)-2-({(2S)-3-[(R)-[(1R)-1-({(4S)-4-amino-5-[(2S)-2-cyanopyrrolidin-1-yl]-5-oxopentanoyl}amino)ethyl](hydroxy)phosphoryl]-2-benzylpropanoyl}amino)propanoic acid


Mass: 549.556 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H36N5O7P
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 291 / Source method: isolated from a natural source / Formula: H2O

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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: 2.34 Å3/Da / Density % sol: 47.45 %
Crystal growTemperature: 294 K / Method: vapor diffusion / pH: 7.5
Details: 25% PEG 3350, 200mM ammonium sulfate, pH 7.5, VAPOR DIFFUSION, temperature 294K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: ENRAF-NONIUS FR591 / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Aug 14, 2003 / Details: mirrors
RadiationMonochromator: OSMIC Mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.05→20 Å / Num. all: 43955 / Num. obs: 43955 / % possible obs: 93.2 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Rsym value: 0.062 / Net I/σ(I): 10.7
Reflection shellResolution: 2.05→2.12 Å / Rmerge(I) obs: 0.515 / Mean I/σ(I) obs: 1.8 / Rsym value: 0.515 / % possible all: 85.6

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
MAR345dtbdata collection
DENZOdata reduction
SCALEPACKdata scaling
MERLOTphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1DTM

1dtm


Resolution: 2.05→20 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.902 / SU B: 5.91 / SU ML: 0.158 / Cross valid method: THROUGHOUT / σ(F): 1 / σ(I): 1 / ESU R: 0.255 / ESU R Free: 0.216 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26766 2227 5.1 %RANDOM
Rwork0.20672 ---
obs0.20976 41720 93.27 %-
all-43955 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 34.342 Å2
Baniso -1Baniso -2Baniso -3
1-0.08 Å20.04 Å20 Å2
2--0.08 Å20 Å2
3----0.11 Å2
Refinement stepCycle: LAST / Resolution: 2.05→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5595 0 81 291 5967
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0215803
X-RAY DIFFRACTIONr_bond_other_d0.0050.025070
X-RAY DIFFRACTIONr_angle_refined_deg0.7371.9577857
X-RAY DIFFRACTIONr_angle_other_deg0.542311841
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.6845695
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.040.2845
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.026447
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021158
X-RAY DIFFRACTIONr_nbd_refined0.2520.21517
X-RAY DIFFRACTIONr_nbd_other0.2860.26153
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.0940.23211
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2130.2287
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined0.1270.21
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.4740.218
X-RAY DIFFRACTIONr_symmetry_vdw_other0.4780.238
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.4760.26
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.99423467
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.63435584
X-RAY DIFFRACTIONr_scbond_it1.01622336
X-RAY DIFFRACTIONr_scangle_it1.65932273
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.05→2.16 Å / Total num. of bins used: 10 /
RfactorNum. reflection
Rfree0.347 285
Rwork0.268 5460

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