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- PDB-5ji6: Potent, Reversible MetAP2 Inhibitors via FBDD -

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Basic information

Entry
Database: PDB / ID: 5ji6
TitlePotent, Reversible MetAP2 Inhibitors via FBDD
ComponentsMethionine aminopeptidase 2
KeywordsHydrolase4/Hydrolase Inhibitor / Hydrolase / peptidase / metal ion binding / proteolysis / Hydrolase4-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-6KN / : / Methionine aminopeptidase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsDougan, D.R. / Lawson, J.D.
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)41,8395
Polymers41,3561
Non-polymers4834
Water2,378132
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)88.962, 100.100, 99.469
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein Methionine aminopeptidase 2 / 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
#2: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-6KN / 4-(3-methylpyridin-4-yl)-6-(trifluoromethyl)-1H-indazole


Mass: 277.245 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H10F3N3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 132 / 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: 2.68 Å3/Da / Density % sol: 54.06 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.9
Details: 24.% PEG MME 2000, 0.05M MES pH 5.9, 0.0175M Ammonium Sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.9765 Å
DetectorType: MARMOSAIC 325 mm CCD / 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: 2.15→50 Å / Num. obs: 24715 / % possible obs: 99.8 % / Redundancy: 5.5 % / Rmerge(I) obs: 0.076 / Χ2: 1.071 / Net I/av σ(I): 23.083 / Net I/σ(I): 8.1 / Num. measured all: 135595
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.15-2.194.90.916198.9
2.19-2.235.20.784199.8
2.23-2.275.40.7481100
2.27-2.325.50.6221100
2.32-2.375.60.6031100
2.37-2.425.60.5051100
2.42-2.485.60.4711100
2.48-2.555.60.3711100
2.55-2.625.60.2951100
2.62-2.715.60.2761100
2.71-2.815.50.2341100
2.81-2.925.60.1641100
2.92-3.055.60.131100
3.05-3.215.60.0931100
3.21-3.415.60.0711100
3.41-3.685.60.053199.9
3.68-4.055.50.043199.8
4.05-4.635.50.034199.8
4.63-5.835.50.033199.7
5.83-505.20.028198.6

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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: 2.15→30 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.951 / SU B: 12.023 / SU ML: 0.154 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.21 / ESU R Free: 0.182
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2297 1250 5.1 %RANDOM
Rwork0.1821 ---
obs0.1844 23252 99.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 147.27 Å2 / Biso mean: 54.495 Å2 / Biso min: 23.89 Å2
Baniso -1Baniso -2Baniso -3
1-3.87 Å20 Å20 Å2
2---3.85 Å20 Å2
3----0.02 Å2
Refinement stepCycle: final / Resolution: 2.15→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2890 0 27 132 3049
Biso mean--68.57 53.17 -
Num. residues----368
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0192985
X-RAY DIFFRACTIONr_angle_refined_deg1.1781.9724048
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8425368
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.13924.412136
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.46315516
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.131518
X-RAY DIFFRACTIONr_chiral_restr0.0790.2442
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212272
LS refinement shellResolution: 2.15→2.206 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.378 115 -
Rwork0.29 1660 -
all-1775 -
obs--99.61 %
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)
13.0571-0.2261-0.08753.3868-0.51911.5589-0.0817-0.2263-0.6708-1.2493-0.07290.59260.60870.08610.15450.59250.0368-0.11750.12590.00040.28919.893212.20141.9128
20.3480.4219-0.6113.2136-0.50741.1293-0.19080.07120.0376-0.82580.21440.64440.387-0.0588-0.02360.34220.0041-0.19380.1259-0.03660.178221.577917.07292.7056
30.5219-0.04720.38873.703-0.61041.60980.08680.0150.0203-0.1043-0.03310.09430.03050.0983-0.05380.0190.00160.00470.1004-0.01490.023730.657628.670514.0506
40.6491-0.10490.29643.3976-0.331.9017-0.0056-0.1275-0.13380.27680.09840.99760.1988-0.3178-0.09280.13-0.06970.05410.14840.04110.337516.94513.243723.488
50.6637-0.1030.97692.8782-0.93893.51410.0264-0.1641-0.01650.40610.09921.09490.0437-0.5316-0.12560.1297-0.02690.13640.16770.03330.461414.88521.281622.8952
60.0743-0.49430.03373.7707-1.2872.7664-0.0263-0.0013-0.13670.31490.19280.9857-0.3254-0.2826-0.16650.04730.03220.07110.13810.01540.305416.957141.490915.0949
70.2176-1.0090.00245.0454-0.42142.38980.1108-0.0202-0.0761-0.24280.13040.6033-0.3473-0.1701-0.24130.18740.02160.03440.1212-0.00120.236320.488647.95065.7046
80.3145-0.29150.23823.2962-0.72491.4970.0962-0.0205-0.00130.04610.02330.6264-0.0116-0.1259-0.11940.0389-0.01040.02810.0938-0.00480.140222.219431.663914.8877
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A110 - 149
2X-RAY DIFFRACTION2A150 - 189
3X-RAY DIFFRACTION3A190 - 269
4X-RAY DIFFRACTION4A270 - 309
5X-RAY DIFFRACTION5A310 - 374
6X-RAY DIFFRACTION6A375 - 394
7X-RAY DIFFRACTION7A395 - 414
8X-RAY DIFFRACTION8A415 - 478

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