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- PDB-4cth: Neprilysin variant G399V,G714K in complex with phosphoramidon -

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Basic information

Entry
Database: PDB / ID: 4cth
TitleNeprilysin variant G399V,G714K in complex with phosphoramidon
ComponentsNEPRILYSIN
KeywordsTRANSFERASE / AMYLOID BETA / ALZHEIMER'S DISEASE / ENZYME ENGINEERING
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 / secretory granule membrane / placenta development / kidney 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 / dendrite / neuronal cell body / synapse / 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
PHOSPHORAMIDON / Chem-RDF / Neprilysin
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsWebster, C.I. / Burrell, M. / Olsson, L. / Fowler, S.B. / Digby, S. / Sandercock, A. / Snijder, A. / Tebbe, J. / Haupts, U. / Grudzinska, J. ...Webster, C.I. / Burrell, M. / Olsson, L. / Fowler, S.B. / Digby, S. / Sandercock, A. / Snijder, A. / Tebbe, J. / Haupts, U. / Grudzinska, J. / Jermutus, L. / Andersson, C.
CitationJournal: Plos One / Year: 2014
Title: Engineering Neprilysin Activity and Specificity to Create a Novel Therapeutic for Alzheimer'S Disease.
Authors: Webster, C.I. / Burrell, M. / Olsson, L. / Fowler, S.B. / Digby, S. / Sandercock, A. / Snijder, A. / Tebbe, J. / Haupts, U. / Grudzinska, J. / Jermutus, L. / Andersson, C.
History
DepositionMar 13, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 13, 2014Provider: repository / Type: Initial release
Revision 1.1Jun 20, 2018Group: Data collection / Structure summary / Category: pdbx_molecule_features
Revision 1.2May 8, 2019Group: Data collection / Derived calculations / Experimental preparation
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / struct_conn
Item: _exptl_crystal_grow.method / _struct_conn.pdbx_leaving_atom_flag
Revision 1.3Jul 29, 2020Group: Data collection / Derived calculations ...Data collection / Derived calculations / Other / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_database_status / pdbx_entity_nonpoly / pdbx_struct_conn_angle / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_database_status.status_code_sf / _pdbx_entity_nonpoly.name / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _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 1.4Dec 20, 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

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Assembly

Deposited unit
A: NEPRILYSIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,42414
Polymers81,4151
Non-polymers2,00913
Water5,855325
1
A: NEPRILYSIN
hetero molecules

A: NEPRILYSIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)166,84828
Polymers162,8292
Non-polymers4,01926
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_554x-y,-y,-z-2/31
Buried area7480 Å2
ΔGint-12.1 kcal/mol
Surface area56830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)108.799, 108.799, 112.942
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

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Protein / Sugars , 2 types, 4 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 / NEP / NEUTRAL ENDOPEPTIDASE / SKIN FIBROBLAST ELASTASE / SFE / CD10


Mass: 81414.531 Da / Num. of mol.: 1 / Fragment: EXTRACELLULAR DOMAIN, RESIDUES 52-750 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / 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 / N-Acetylglucosamine


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

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Non-polymers , 4 types, 335 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-RDF / N-ALPHA-L-RHAMNOPYRANOSYLOXY(HYDROXYPHOSPHINYL)-L-LEUCYL-L-TRYPTOPHAN / / PHOSPHORAMIDON / Phosphoramidon


Type: peptide-like, Glycopeptide / Class: Enzyme inhibitor / Mass: 543.504 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H34N3O10P / References: PHOSPHORAMIDON / Comment: inhibitor*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 325 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsG399V G714K ARE ENGINEERED MUTATIONS

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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: 2.3 Å3/Da / Density % sol: 48 % / Description: NONE
Crystal growMethod: vapor diffusion, hanging drop / pH: 7 / Details: HANGING DROP, pH 7.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.917
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Mar 1, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.917 Å / Relative weight: 1
ReflectionResolution: 2.15→45 Å / Num. obs: 42405 / % possible obs: 99.8 % / Observed criterion σ(I): 0 / Redundancy: 9.2 % / Biso Wilson estimate: 42.37 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 16.4
Reflection shellResolution: 2.15→2.21 Å / Redundancy: 8 % / Rmerge(I) obs: 1.27 / Mean I/σ(I) obs: 16.4 / % possible all: 99.8

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Processing

Software
NameVersionClassification
BUSTER2.11.1refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1DMT

1dmt


Resolution: 2.15→31.48 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.9121 / SU R Cruickshank DPI: 0.26 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.268 / SU Rfree Blow DPI: 0.212 / SU Rfree Cruickshank DPI: 0.212
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. RESIDUE TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY=NAG ZN GOL. NUMBER OF ATOMS WITH PROPER CCP4 ATOM TYPE=5973. NUMBER WITH APPROX DEFAULT CCP4 ATOM ...Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. RESIDUE TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY=NAG ZN GOL. NUMBER OF ATOMS WITH PROPER CCP4 ATOM TYPE=5973. NUMBER WITH APPROX DEFAULT CCP4 ATOM TYPE=90. NUMBER TREATED BY BAD NON-BONDED CONTACTS=1.
RfactorNum. reflection% reflectionSelection details
Rfree0.2614 2138 5.05 %RANDOM
Rwork0.2095 ---
obs0.2122 42359 99.79 %-
Displacement parametersBiso mean: 47.47 Å2
Baniso -1Baniso -2Baniso -3
1--4.1609 Å20 Å20 Å2
2---4.1609 Å20 Å2
3---8.3217 Å2
Refine analyzeLuzzati coordinate error obs: 0.332 Å
Refinement stepCycle: LAST / Resolution: 2.15→31.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5611 0 128 325 6064
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015859HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.097926HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2063SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes184HARMONIC2
X-RAY DIFFRACTIONt_gen_planes827HARMONIC5
X-RAY DIFFRACTIONt_it5859HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.73
X-RAY DIFFRACTIONt_other_torsion18.93
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion753SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact7005SEMIHARMONIC4
LS refinement shellResolution: 2.15→2.21 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.4434 171 5.53 %
Rwork0.4097 2920 -
all0.4115 3091 -
obs--99.79 %

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