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- PDB-3v6s: Discovery of potent and selective covalent inhibitors of JNK -

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Basic information

Entry
Database: PDB / ID: 3v6s
TitleDiscovery of potent and selective covalent inhibitors of JNK
ComponentsMitogen-activated protein kinase 10
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / KINASE FOLD / APOPTOSIS / MAP KINASE / CYS modification / JNK / Phosphorylation / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


JUN kinase activity / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / MAP kinase kinase activity / response to light stimulus / mitogen-activated protein kinase / JNK cascade / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / FCERI mediated MAPK activation / regulation of circadian rhythm ...JUN kinase activity / Activation of the AP-1 family of transcription factors / Fc-epsilon receptor signaling pathway / MAP kinase kinase activity / response to light stimulus / mitogen-activated protein kinase / JNK cascade / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / FCERI mediated MAPK activation / regulation of circadian rhythm / cellular senescence / rhythmic process / Oxidative Stress Induced Senescence / protein phosphorylation / protein serine kinase activity / signal transduction / mitochondrion / nucleoplasm / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Mitogen-activated protein (MAP) kinase, JNK / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain ...Mitogen-activated protein (MAP) kinase, JNK / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-0F0 / Mitogen-activated protein kinase 10
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.97 Å
AuthorsPark, H. / Laughlin, J.D. / LoGrasso, P.V.
CitationJournal: Chem.Biol. / Year: 2012
Title: Discovery of potent and selective covalent inhibitors of JNK.
Authors: Zhang, T. / Inesta-Vaquera, F. / Niepel, M. / Zhang, J. / Ficarro, S.B. / Machleidt, T. / Xie, T. / Marto, J.A. / Kim, N. / Sim, T. / Laughlin, J.D. / Park, H. / LoGrasso, P.V. / Patricelli, ...Authors: Zhang, T. / Inesta-Vaquera, F. / Niepel, M. / Zhang, J. / Ficarro, S.B. / Machleidt, T. / Xie, T. / Marto, J.A. / Kim, N. / Sim, T. / Laughlin, J.D. / Park, H. / LoGrasso, P.V. / Patricelli, M. / Nomanbhoy, T.K. / Sorger, P.K. / Alessi, D.R. / Gray, N.S.
History
DepositionDec 20, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 1, 2012Provider: repository / Type: Initial release
Revision 1.1Jul 25, 2012Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mitogen-activated protein kinase 10
B: Mitogen-activated protein kinase 10
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,1114
Polymers84,1192
Non-polymers9912
Water3,873215
1
A: Mitogen-activated protein kinase 10
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5552
Polymers42,0601
Non-polymers4961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Mitogen-activated protein kinase 10
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5552
Polymers42,0601
Non-polymers4961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)109.491, 156.262, 43.884
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Mitogen-activated protein kinase 10 / MAP kinase 10 / MAPK 10 / MAP kinase p49 3F12 / Stress-activated protein kinase 1b / SAPK1b / ...MAP kinase 10 / MAPK 10 / MAP kinase p49 3F12 / Stress-activated protein kinase 1b / SAPK1b / Stress-activated protein kinase JNK3 / c-Jun N-terminal kinase 3


Mass: 42059.676 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK10, JNK3, JNK3A, PRKM10, SAPK1B / Production host: Escherichia coli (E. coli)
References: UniProt: P53779, mitogen-activated protein kinase
#2: Chemical ChemComp-0F0 / 3-{[4-(dimethylamino)butanoyl]amino}-N-(4-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide


Mass: 495.576 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H29N7O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 215 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsTHE ATOMS C33 OF LIGAND 0F0 IS COVALENTLY LINKED TO SG ATOM GROUP OF C154. THE STARTING MATERIAL OF ...THE ATOMS C33 OF LIGAND 0F0 IS COVALENTLY LINKED TO SG ATOM GROUP OF C154. THE STARTING MATERIAL OF LIGAND 0F0 HAS A DOUBLE BOND BETWEEN C33 AND C32 ATOM GROUPS ((E)-3-(4-(DIMETHYLAMINO)BUT-2-ENAMIDO)-N-(4-((4-(PYRIDIN-3-YL)PYRIMIDIN-2- YL)AMI NO)PHENYL)BENZAMIDE ) AND UNDERGOES TO NUCLEOPHILIC ATTACK WITH RESIDUES C154.
Sequence detailsTHE SEQUENCE CORRESPONDS TO ISOFORM 3 OF MITOGEN-ACTIVATED PROTEIN KINASE 10 UNP ENTRY P53779-3.

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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: 2.22 Å3/Da / Density % sol: 44.68 %
Crystal growTemperature: 277 K / pH: 7
Details: 50 mM HEPES pH 7.0, 100 mM NaCl, 5% glycerol, 5 mM TCEP, 0.4 mM Zwittergent 3-14), VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

Diffraction
IDMean temperature (K)Crystal-ID
11001
21
Diffraction source
SourceSiteBeamlineIDWavelength
SYNCHROTRONSSRL BL11-110.97945
2
Detector
TypeIDDetectorDateDetails
MARMOSAIC 325 mm CCD1CCDApr 28, 2011RH COATED FLAT MIRROR
2
Radiation
IDMonochromatorProtocolMonochromatic (M) / Laue (L)Scattering typeWavelength-ID
1SIDE SCATTERING BENT CUBE-ROOT I -BEAM SINGLE CRYSTALSINGLE WAVELENGTHMx-ray1
2ASYMMETRIC CUT 4.965 DEGSx-ray1
Radiation wavelengthWavelength: 0.97945 Å / Relative weight: 1
ReflectionResolution: 2.97→156.26 Å / Num. obs: 16326 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 7.1 % / Biso Wilson estimate: 66.1 Å2 / Rmerge(I) obs: 0.129 / Net I/σ(I): 13.2
Reflection shellResolution: 2.97→3.13 Å / % possible all: 100

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Processing

Software
NameVersionClassification
Blu-Icedata collection
MOLREPphasing
BUSTER2.9.2refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.97→27.62 Å / Cor.coef. Fo:Fc: 0.889 / Cor.coef. Fo:Fc free: 0.845 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.263 1009 6.21 %RANDOM
Rwork0.216 ---
obs0.219 16238 --
all-116672 --
Displacement parametersBiso mean: 48.05 Å2
Baniso -1Baniso -2Baniso -3
1--10.9988 Å20 Å20 Å2
2--8.3003 Å20 Å2
3---2.6985 Å2
Refine analyzeLuzzati coordinate error obs: 0.4 Å
Refinement stepCycle: LAST / Resolution: 2.97→27.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5478 0 74 215 5767
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015697HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.197732HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2598SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes146HARMONIC2
X-RAY DIFFRACTIONt_gen_planes806HARMONIC5
X-RAY DIFFRACTIONt_it5611HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.06
X-RAY DIFFRACTIONt_other_torsion3.2
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion734SEMIHARMONIC5
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_contact6664SEMIHARMONIC4
LS refinement shellResolution: 2.97→3.17 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.2786 196 6.79 %
Rwork0.2321 2691 -
all0.2352 2887 -
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)
10.66390.247-0.64824.1634-0.19426.9611-0.06340.0879-0.0165-0.0145-0.07050.0803-0.0213-0.19430.134-0.08450.0344-0.0193-0.07760.0145-0.059213.2886-12.4764-35.6181
21.2827-1.5098-2.73693.9151-2.82910-0.02380.0394-0.02520.00210.0293-0.03430.12850.1059-0.00550.03980.0929-0.092-0.05730.07330.09186.8429-27.0489-22.2911
30.0190.58420.84831.0563-0.16271.1819-0.15990.0270.15460.01480.02220.1452-0.2307-0.12940.1377-0.0678-0.0013-0.0129-0.0029-0.0017-0.074819.9353-15.3881-19.9383
400.60230.60473.67880.69440.4649-0.0111-0.1884-0.12180.07490.037-0.03480.0082-0.1612-0.02590.00030.00730.01480.00050.0344-0.050718.4201-22.0599-14.9371
52.54670.1279-0.14421.67410.36410.64460.0229-0.0158-0.3621-0.04910.0257-0.06850.20970.0037-0.0486-0.0171-0.026-0.021-0.05970.0248-0.12333.0936-27.3826-7.4963
600.4409-2.87490-0.4851.3175-0.007-0.12790.12630.0606-0.0142-0.00110.1147-0.05860.0212-0.0520.09470.0260.02730.10060.0173-0.5765-22.4109-19.4557
74.9176-2.82540.24121.5932-0.23496.37850.015-0.15890.00230.25540.0978-0.2520.16350.2768-0.1129-0.27950.01680.1494-0.1629-0.07410.287435.5794-58.9282-25.9593
80-0.2291-2.85440.9421-0.91122.31930.0072-0.0095-0.07640.0459-0.03410.0194-0.07950.04720.02690.08770.01750.0357-0.0349-0.0114-0.025721.2082-71.0345-31.4416
90.443-0.63080.27714.25361.91991.4281-0.00120.24430.1088-0.3756-0.0223-0.54180.19560.09840.0235-0.104-0.05040.072-0.14440.011-0.048118.5704-54.9721-25.0172
103.0721.3985-1.575401.17871.61560.01220.0564-0.0431-0.084-0.115-0.0230.0388-0.02330.10290.1145-0.0308-0.0874-0.11130.114-0.014115.1491-55.6793-21.1128
111.67270.7498-0.70223.0823-1.2721.1756-0.1124-0.00360.03530.11260.0520.16440.1051-0.04550.0604-0.02250.0037-0.02-0.1233-0.0099-0.1046-0.0515-57.2888-12.9731
120.0633-2.72231.73892.52072.31152.1317-0.0045-0.09450.0784-0.12270.04520.0376-0.0586-0.2088-0.04070.24050.1520.0563-0.04570.0917-0.187119.9952-71.2238-40.7786
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|45 - 96}A45 - 96
2X-RAY DIFFRACTION2{A|97 - 111}A97 - 111
3X-RAY DIFFRACTION3{A|112 - 199}A112 - 199
4X-RAY DIFFRACTION4{A|200 - 219}A200 - 219
5X-RAY DIFFRACTION5{A|225 - 375}A225 - 375
6X-RAY DIFFRACTION6{A|379 - 401}A379 - 401
7X-RAY DIFFRACTION7{B|45 - 92}B45 - 92
8X-RAY DIFFRACTION8{B|93 - 111}B93 - 111
9X-RAY DIFFRACTION9{B|112 - 187}B112 - 187
10X-RAY DIFFRACTION10{B|188 - 211}B188 - 211
11X-RAY DIFFRACTION11{B|225 - 380}B225 - 380
12X-RAY DIFFRACTION12{B|381 - 401}B381 - 401

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