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- PDB-5jfr: Potent, Reversible MetAP2 Inhibitors via Fragment Based Drug Discovery -

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Basic information

Entry
Database: PDB / ID: 5jfr
TitlePotent, Reversible MetAP2 Inhibitors via Fragment Based Drug Discovery
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-6KP / : / Methionine aminopeptidase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 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 2.
Authors: McBride, C. / Cheruvallath, Z. / Komandla, M. / Tang, M. / Farrell, P. / Lawson, J.D. / Vanderpool, D. / Wu, Y. / Dougan, D.R. / Plonowski, A. / Holub, C. / Larson, C.
History
DepositionApr 19, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 25, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 15, 2016Group: Database references

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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)41,9126
Polymers41,3561
Non-polymers5565
Water6,125340
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)89.644, 100.816, 99.445
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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 / 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, 345 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-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-6KP / 7-fluoro-4-(5-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-2,4-dihydropyrazolo[4,3-b]indole


Mass: 306.297 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H11FN6
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 340 / 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: 2.72 Å3/Da / Density % sol: 54.72 % / Mosaicity: 0.336 °
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 40% MPD, 0.1M Hepes pH 7.0

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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: 1.6→50 Å / Num. obs: 59409 / % possible obs: 99.9 % / Redundancy: 7.2 % / Rmerge(I) obs: 0.06 / Χ2: 1.008 / Net I/av σ(I): 29.74 / Net I/σ(I): 11.2 / Num. measured all: 430107
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
1.6-1.636.50.82199.8
1.63-1.6670.7731100
1.66-1.697.30.7091100
1.69-1.727.30.5941100
1.72-1.767.40.5151100
1.76-1.87.30.4151100
1.8-1.857.40.3561100
1.85-1.97.40.3081100
1.9-1.957.30.2371100
1.95-2.027.40.1711100
2.02-2.097.40.1341100
2.09-2.177.40.111100
2.17-2.277.40.0931100
2.27-2.397.40.0761100
2.39-2.547.40.0731100
2.54-2.747.30.0731100
2.74-3.017.10.0661100
3.01-3.457.10.0521100
3.45-4.347.10.0291100
4.34-507.10.024199.2

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.7.0025refinement
PDB_EXTRACT3.2data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→30 Å / Cor.coef. Fo:Fc: 0.981 / Cor.coef. Fo:Fc free: 0.969 / SU B: 3.463 / SU ML: 0.052 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.077 / ESU R Free: 0.067
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.1714 2997 5 %RANDOM
Rwork0.1358 ---
obs0.1376 56379 99.85 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 140.59 Å2 / Biso mean: 34.875 Å2 / Biso min: 15.6 Å2
Baniso -1Baniso -2Baniso -3
1-2.33 Å20 Å20 Å2
2---2.46 Å20 Å2
3---0.13 Å2
Refinement stepCycle: final / Resolution: 1.6→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2876 0 37 340 3253
Biso mean--36.81 45.99 -
Num. residues----366
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192994
X-RAY DIFFRACTIONr_bond_other_d0.0010.022809
X-RAY DIFFRACTIONr_angle_refined_deg1.2111.9744057
X-RAY DIFFRACTIONr_angle_other_deg0.7373.0016495
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0625364
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.124.453137
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.98515520
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.2171518
X-RAY DIFFRACTIONr_chiral_restr0.070.2446
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213369
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02650
X-RAY DIFFRACTIONr_rigid_bond_restr2.19335802
X-RAY DIFFRACTIONr_sphericity_free36.1075118
X-RAY DIFFRACTIONr_sphericity_bonded9.26555964
LS refinement shellResolution: 1.601→1.643 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.237 225 -
Rwork0.219 4065 -
all-4290 -
obs--98.89 %
Refinement TLS params.Method: refined / Origin x: 21.849 Å / Origin y: -25.419 Å / Origin z: -13.436 Å
111213212223313233
T0.0377 Å20.0085 Å20.0404 Å2-0.0852 Å20.0012 Å2--0.1181 Å2
L0.2722 °20.3341 °2-0.0795 °2-2.7225 °2-0.6285 °2--0.8421 °2
S0.0913 Å °0.0055 Å °0.0704 Å °0.2168 Å °0.0258 Å °0.4891 Å °-0.083 Å °-0.06 Å °-0.117 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A110 - 215
2X-RAY DIFFRACTION1A216 - 269
3X-RAY DIFFRACTION1A270 - 321
4X-RAY DIFFRACTION1A322 - 478
5X-RAY DIFFRACTION1A501
6X-RAY DIFFRACTION1A502
7X-RAY DIFFRACTION1A505

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