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- PDB-5jhu: Potent, Reversible MetAP2 Inhibitors via FBDD -

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Basic information

Entry
Database: PDB / ID: 5jhu
TitlePotent, Reversible MetAP2 Inhibitors via FBDD
ComponentsMethionine aminopeptidase 2Methionyl aminopeptidase
KeywordsHydrolase/Hydrolase Inhibitor / Hydrolase / peptidase / metal ion binding / proteolysis / Hydrolase-Hydrolase Inhibitor complex
Function / homology
Function and homology information


N-terminal protein amino acid modification / peptidyl-methionine modification / initiator methionyl aminopeptidase activity / methionyl aminopeptidase / 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 / initiator methionyl aminopeptidase activity / methionyl aminopeptidase / 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 / Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain ...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-6KO / : / Methionine aminopeptidase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsDougan, D.R.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 1.
Authors: Cheruvallath, Z. / Tang, M. / McBride, C. / Komandla, M. / Miura, J. / Ton-Nu, T. / Erikson, P. / Feng, J. / Farrell, P. / Lawson, J.D. / Vanderpool, D. / Wu, Y. / Dougan, D.R. / Plonowski, ...Authors: Cheruvallath, Z. / Tang, M. / McBride, C. / Komandla, M. / Miura, J. / Ton-Nu, T. / Erikson, P. / Feng, J. / Farrell, P. / Lawson, J.D. / Vanderpool, D. / Wu, Y. / Dougan, D.R. / Plonowski, A. / Holub, C. / Larson, C.
History
DepositionApr 21, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 25, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 15, 2016Group: Database references
Revision 1.2Nov 22, 2017Group: Database references / Derived calculations / Refinement description
Category: citation / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _pdbx_struct_oper_list.symmetry_operation / _software.classification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Methionine aminopeptidase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,9896
Polymers41,3561
Non-polymers6335
Water5,639313
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)90.181, 100.964, 100.126
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-913-

HOH

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 41355.977 Da / Num. of mol.: 1 / Fragment: UNP residues 87-455
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: METAP2, MNPEP, P67EIF2 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): sf9 / References: UniProt: P50579, methionyl aminopeptidase

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Non-polymers , 5 types, 318 molecules

#2: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-6KO / [(2R)-1-([1,2,4]triazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-2-yl]methyl 2-methoxybenzoate


Mass: 353.375 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H19N5O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 313 / 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: 2.76 Å3/Da / Density % sol: 55.36 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.9 / Details: 30% MPD, 0.05M MES pH 5.9

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9765 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 19, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 1.7→50 Å / Num. obs: 47975 / % possible obs: 95.5 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.061 / Χ2: 1.012 / Net I/av σ(I): 26.344 / Net I/σ(I): 17 / Num. measured all: 314819
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
1.7-1.733.60.333166.3
1.73-1.763.90.318174.8
1.76-1.794.30.288182.6
1.79-1.834.80.288190.2
1.83-1.875.40.269195.8
1.87-1.916.50.229199.8
1.91-1.967.30.1881100
1.96-2.027.40.1471100
2.02-2.077.40.1231100
2.07-2.147.40.1051100
2.14-2.227.40.091100
2.22-2.317.40.0821100
2.31-2.417.40.0721100
2.41-2.547.30.0661100
2.54-2.77.30.061100
2.7-2.917.30.0551100
2.91-3.27.20.0551100
3.2-3.666.70.055199.9
3.66-4.616.50.051199.9
4.61-506.60.043198.8

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Processing

Software
NameVersionClassification
REFMAC5.7.0025refinement
HKL-2000data scaling
PDB_EXTRACT3.2data extraction
XFITdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→30 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.961 / SU B: 4.218 / SU ML: 0.059 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.139 / ESU R Free: 0.095
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.1809 2148 5.1 %RANDOM
Rwork0.1381 ---
obs0.1402 40033 98.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 108.77 Å2 / Biso mean: 31.468 Å2 / Biso min: 15.36 Å2
Baniso -1Baniso -2Baniso -3
1-3.28 Å20 Å20 Å2
2---2.09 Å20 Å2
3----1.19 Å2
Refinement stepCycle: final / Resolution: 1.8→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2848 0 42 313 3203
Biso mean--36.82 41.26 -
Num. residues----362
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0192998
X-RAY DIFFRACTIONr_angle_refined_deg1.2341.9734069
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6025374
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.71324.275138
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.69215518
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.8791519
X-RAY DIFFRACTIONr_chiral_restr0.080.2446
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212313
X-RAY DIFFRACTIONr_rigid_bond_restr1.64732998
X-RAY DIFFRACTIONr_sphericity_free23.9955111
X-RAY DIFFRACTIONr_sphericity_bonded11.09853132
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.221 145 -
Rwork0.18 2648 -
all-2793 -
obs--90.65 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.12931.4182-0.2611.3164-0.12870.9550.0203-0.0284-0.191-0.4668-0.0715-0.02040.30270.340.05120.43540.1345-0.02840.1668-0.01390.0317-14.0909-33.3113-2.7673
21.09680.70880.44090.75320.26470.20550.0529-0.026-0.0268-0.1803-0.00840.0320.05380.0327-0.04450.18010.0028-0.07480.0979-0.00660.0875-28.8137-36.94443.4004
30.13380.01950.23620.6488-0.23010.5630.02870.00320.0195-0.0247-0.028-0.0140.02210.0312-0.00070.0817-0.00490.00950.12250.00530.1111-12.4267-20.531114.6969
40.06230.05650.1860.50410.03340.60580.0391-0.01080.00350.0119-0.00310.08690.1043-0.0392-0.0360.0869-0.0325-0.0050.1190.02110.1246-25.6091-34.810620.7677
50.04680.03690.14030.5647-0.1780.64590.0248-0.00240.02250.1219-0.01310.2332-0.0227-0.0353-0.01170.067-0.02840.01540.13560.02720.1377-29.411-29.123921.1808
60.003-0.00740.01011.3173-0.97580.9739-0.0043-0.0181-0.00120.15350.06250.2692-0.1228-0.0687-0.05820.08250.020.03130.11290.00690.1651-27.3472-9.77317.6466
70.0597-0.1799-0.05011.1842-0.34940.4980.0007-0.0089-0.0146-0.00820.02360.0103-0.0577-0.0208-0.02420.09620.0140.01540.09950.00040.1192-21.6214-4.259110.4931
80.10610.18910.0730.4155-0.04260.5440.0498-0.00370.0230.05450.03940.10690.0844-0.0262-0.08920.1005-0.0132-0.01780.11880.01120.1269-23.8237-31.243516.3501
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A110 - 135
2X-RAY DIFFRACTION2A136 - 186
3X-RAY DIFFRACTION3A187 - 256
4X-RAY DIFFRACTION4A257 - 310
5X-RAY DIFFRACTION5A311 - 368
6X-RAY DIFFRACTION6A369 - 396
7X-RAY DIFFRACTION7A397 - 444
8X-RAY DIFFRACTION8A445 - 478

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