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- PDB-5eak: Optimization of Microtubule Affinity Regulating Kinase (MARK) Inh... -

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Basic information

Entry
Database: PDB / ID: 5eak
TitleOptimization of Microtubule Affinity Regulating Kinase (MARK) Inhibitors with Improved Physical Properties
ComponentsSerine/threonine-protein kinase MARK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / CATALYTIC DOMAIN / PROTEIN-SERINE-THREONINE KINASES / KINASE INHIBITOR / SERINE-THREONINE KINASES / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
Function / homology
Function and homology information


establishment or maintenance of cell polarity regulating cell shape / microtubule bundle / regulation of microtubule binding / mitochondrion localization / autophagy of mitochondrion / tau-protein kinase / establishment or maintenance of epithelial cell apical/basal polarity / regulation of axonogenesis / establishment of cell polarity / tau-protein kinase activity ...establishment or maintenance of cell polarity regulating cell shape / microtubule bundle / regulation of microtubule binding / mitochondrion localization / autophagy of mitochondrion / tau-protein kinase / establishment or maintenance of epithelial cell apical/basal polarity / regulation of axonogenesis / establishment of cell polarity / tau-protein kinase activity / axon development / activation of protein kinase activity / protein kinase activator activity / regulation of cytoskeleton organization / lateral plasma membrane / regulation of microtubule cytoskeleton organization / actin filament / peptidyl-threonine phosphorylation / neuron migration / tau protein binding / Wnt signaling pathway / microtubule cytoskeleton organization / positive regulation of neuron projection development / peptidyl-serine phosphorylation / protein autophosphorylation / non-specific serine/threonine protein kinase / intracellular signal transduction / cadherin binding / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / lipid binding / dendrite / magnesium ion binding / mitochondrion / RNA binding / nucleoplasm / ATP binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
: / Kinase associated domain 1 (KA1) / Kinase associated domain 1 / Kinase associated domain 1 (KA1) profile. / KA1 domain/Ssp2, C-terminal / UBA/TS-N domain / Ubiquitin associated domain / Ubiquitin-associated domain / Ubiquitin-associated domain (UBA) profile. / Serine/threonine-protein kinase, active site ...: / Kinase associated domain 1 (KA1) / Kinase associated domain 1 / Kinase associated domain 1 (KA1) profile. / KA1 domain/Ssp2, C-terminal / UBA/TS-N domain / Ubiquitin associated domain / Ubiquitin-associated domain / Ubiquitin-associated domain (UBA) profile. / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-24R / Serine/threonine-protein kinase MARK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.8 Å
AuthorsSu, H.P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties.
Authors: Sloman, D.L. / Noucti, N. / Altman, M.D. / Chen, D. / Mislak, A.C. / Szewczak, A. / Hayashi, M. / Warren, L. / Dellovade, T. / Wu, Z. / Marcus, J. / Walker, D. / Su, H.P. / Edavettal, S.C. / ...Authors: Sloman, D.L. / Noucti, N. / Altman, M.D. / Chen, D. / Mislak, A.C. / Szewczak, A. / Hayashi, M. / Warren, L. / Dellovade, T. / Wu, Z. / Marcus, J. / Walker, D. / Su, H.P. / Edavettal, S.C. / Munshi, S. / Hutton, M. / Nuthall, H. / Stanton, M.G.
History
DepositionOct 16, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 17, 2016Provider: repository / Type: Initial release
Revision 1.1Aug 24, 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.name
Revision 1.3Mar 6, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Serine/threonine-protein kinase MARK2
B: Serine/threonine-protein kinase MARK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,5084
Polymers75,6652
Non-polymers8432
Water1086
1
A: Serine/threonine-protein kinase MARK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2542
Polymers37,8331
Non-polymers4221
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Serine/threonine-protein kinase MARK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2542
Polymers37,8331
Non-polymers4221
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)118.739, 118.739, 106.592
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61

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Components

#1: Protein Serine/threonine-protein kinase MARK2 / ELKL motif kinase 1 / EMK-1 / MAP/microtubule affinity-regulating kinase 2 / PAR1 homolog / PAR1 ...ELKL motif kinase 1 / EMK-1 / MAP/microtubule affinity-regulating kinase 2 / PAR1 homolog / PAR1 homolog b / Par1b


Mass: 37832.719 Da / Num. of mol.: 2 / Fragment: CATALYTIC DOMAIN (UNP RESIDUES 39-364)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MARK2, EMK1 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: Q7KZI7, non-specific serine/threonine protein kinase, tau-protein kinase
#2: Chemical ChemComp-24R / N-[(1S,2R)-2-aminocyclohexyl]-4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophene-2-carboxamide


Mass: 421.519 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H23N7OS
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 6 / 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: 2.87 Å3/Da / Density % sol: 57.09 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1M BIS-TRIS PH 6.5, 14% PEG3350, 200MM AMM.SULFATE
PH range: 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jul 11, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→30 Å / Num. obs: 21123 / % possible obs: 100 % / Redundancy: 9.6 % / Rmerge(I) obs: 0.104 / Net I/σ(I): 9.1
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 9.6 % / Rmerge(I) obs: 0.442 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing
PHENIX1.6.4_486refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.8→29.68 Å / SU ML: 0.42 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.89 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.254 1084 5.15 %
Rwork0.195 --
obs0.198 21064 99.8 %
Solvent computationShrinkage radii: 0.83 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 16.78 Å2 / ksol: 0.35 e/Å3
Displacement parametersBiso mean: 33.29 Å2
Baniso -1Baniso -2Baniso -3
1--0.4328 Å20 Å20 Å2
2---0.4328 Å20 Å2
3---0.8655 Å2
Refinement stepCycle: LAST / Resolution: 2.8→29.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4915 0 60 6 4981
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0095081
X-RAY DIFFRACTIONf_angle_d1.2186844
X-RAY DIFFRACTIONf_dihedral_angle_d16.6831933
X-RAY DIFFRACTIONf_chiral_restr0.079738
X-RAY DIFFRACTIONf_plane_restr0.004866
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.799-2.92630.36771260.28992465X-RAY DIFFRACTION100
2.9263-3.08050.33681490.25662481X-RAY DIFFRACTION100
3.0805-3.27320.32331330.21412502X-RAY DIFFRACTION100
3.2732-3.52560.23751280.19282488X-RAY DIFFRACTION100
3.5256-3.87970.24341620.17562469X-RAY DIFFRACTION100
3.8797-4.43950.23511300.17192505X-RAY DIFFRACTION100
4.4395-5.58720.19231290.16732507X-RAY DIFFRACTION100
5.5872-29.68640.23911270.19592563X-RAY DIFFRACTION100

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