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- PDB-6qef: CRYSTAL STRUCTURE OF HUMAN METHIONINE AMINOPEPTIDASE-2 IN COMPLEX... -

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Basic information

Entry
Database: PDB / ID: 6qef
TitleCRYSTAL STRUCTURE OF HUMAN METHIONINE AMINOPEPTIDASE-2 IN COMPLEX WITH AN INHIBITOR (S)-3-Hydroxy-2-oxo-1-phenyl-pyrrolidine-3-carboxylic acid 3-chloro-5-fluoro-benzylamide
ComponentsMethionine aminopeptidase 2
KeywordsHYDROLASE / PEPTIDASE / METAL ION BINDING / PROTEOLYSIS / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


N-terminal protein amino acid modification / peptidyl-methionine modification / methionyl aminopeptidase / initiator methionyl aminopeptidase activity / metalloexopeptidase activity / metalloaminopeptidase activity / aminopeptidase activity / protein processing / Inactivation, recovery and regulation of the phototransduction cascade / RNA binding ...N-terminal protein amino acid modification / peptidyl-methionine modification / methionyl aminopeptidase / initiator methionyl aminopeptidase activity / metalloexopeptidase activity / metalloaminopeptidase activity / aminopeptidase activity / protein processing / Inactivation, recovery and regulation of the phototransduction cascade / RNA binding / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Peptidase M24A, methionine aminopeptidase, subfamily 2 / : / Peptidase M24A, methionine aminopeptidase, subfamily 2, binding site / Methionine aminopeptidase subfamily 2 signature. / Peptidase M24, methionine aminopeptidase / Creatine Amidinohydrolase / Creatinase/methionine aminopeptidase superfamily / Peptidase M24 / Metallopeptidase family M24 / Creatinase/aminopeptidase-like ...Peptidase M24A, methionine aminopeptidase, subfamily 2 / : / Peptidase M24A, methionine aminopeptidase, subfamily 2, binding site / Methionine aminopeptidase subfamily 2 signature. / Peptidase M24, methionine aminopeptidase / Creatine Amidinohydrolase / Creatinase/methionine aminopeptidase superfamily / Peptidase M24 / Metallopeptidase family M24 / Creatinase/aminopeptidase-like / Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain / Arc Repressor Mutant, subunit A / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily / Alpha-Beta Complex / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-HZW / : / Methionine aminopeptidase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.79 Å
AuthorsMusil, D. / Heinrich, T. / Lehmann, M.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Discovery and Structure-Based Optimization of Next-Generation Reversible Methionine Aminopeptidase-2 (MetAP-2) Inhibitors.
Authors: Heinrich, T. / Seenisamy, J. / Blume, B. / Bomke, J. / Calderini, M. / Eckert, U. / Friese-Hamim, M. / Kohl, R. / Lehmann, M. / Leuthner, B. / Musil, D. / Rohdich, F. / Zenke, F.T.
History
DepositionJan 7, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 1, 2019Provider: repository / Type: Initial release
Revision 1.1Jun 5, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Aug 14, 2019Group: Data collection / Category: reflns_shell
Item: _reflns_shell.Rmerge_I_obs / _reflns_shell.pdbx_Rrim_I_all
Revision 1.3May 15, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Methionine aminopeptidase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,34510
Polymers42,4701
Non-polymers8759
Water3,351186
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1310 Å2
ΔGint14 kcal/mol
Surface area16280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)88.360, 99.400, 100.600
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Methionine aminopeptidase 2 / MetAP 2 / Initiation factor 2-associated 67 kDa glycoprotein / p67eIF2 / Peptidase M


Mass: 42470.207 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: METAP2, MNPEP, P67EIF2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P50579, methionyl aminopeptidase

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Non-polymers , 5 types, 195 molecules

#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-HZW / (3~{S})-~{N}-[(3-chloranyl-5-fluoranyl-phenyl)methyl]-3-oxidanyl-2-oxidanylidene-1-phenyl-pyrrolidine-3-carboxamide


Mass: 362.783 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H16ClFN2O3
#5: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 186 / 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: 2.6 Å3/Da / Density % sol: 52.7 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 20% METHANOL, 0.1 M CITRATE, PH 6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 22, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.79→40.45 Å / Num. obs: 41485 / % possible obs: 99.5 % / Redundancy: 6.6 % / Biso Wilson estimate: 28.39 Å2 / Rmerge(I) obs: 0.074 / Rrim(I) all: 0.06 / Net I/σ(I): 19.3
Reflection shellResolution: 1.79→1.9 Å / Redundancy: 6.5 % / Rmerge(I) obs: 0.496 / Mean I/σ(I) obs: 3.3 / Num. unique obs: 6442 / Rrim(I) all: 0.596 / % possible all: 96.8

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.79→40.45 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.933 / SU R Cruickshank DPI: 0.103 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.104 / SU Rfree Blow DPI: 0.096 / SU Rfree Cruickshank DPI: 0.096
RfactorNum. reflection% reflectionSelection details
Rfree0.195 2074 5 %RANDOM
Rwork0.175 ---
obs0.176 41480 99.5 %-
Displacement parametersBiso mean: 38.52 Å2
Baniso -1Baniso -2Baniso -3
1--13.651 Å20 Å20 Å2
2--7.9789 Å20 Å2
3---5.6721 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: 1 / Resolution: 1.79→40.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2856 0 53 186 3095
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012995HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.024050HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1052SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes524HARMONIC5
X-RAY DIFFRACTIONt_it2995HARMONIC20
X-RAY DIFFRACTIONt_nbd4SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.76
X-RAY DIFFRACTIONt_other_torsion14.83
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion391SEMIHARMONIC5
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_contact3690SEMIHARMONIC4
LS refinement shellResolution: 1.79→1.81 Å / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2061 -4.94 %
Rwork0.2195 789 -
all0.2188 830 -
obs--82.57 %
Refinement TLS params.Method: refined / Origin x: -23.0108 Å / Origin y: -24.5365 Å / Origin z: 14.0142 Å
111213212223313233
T-0.1282 Å2-0.0025 Å20.0241 Å2--0.1262 Å2-0.0021 Å2---0.0421 Å2
L0.4117 °2-0.1665 °20.01 °2-3.1902 °2-0.5588 °2--0.9445 °2
S0.051 Å °0.0205 Å °-0.052 Å °0.0829 Å °0.0131 Å °0.5063 Å °0.0166 Å °-0.0278 Å °-0.0641 Å °
Refinement TLS groupSelection details: { A|* }

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