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- PDB-7p1l: The MARK3 Kinase Domain Bound To AA-CS-1-008 -

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Basic information

Entry
Database: PDB / ID: 7p1l
TitleThe MARK3 Kinase Domain Bound To AA-CS-1-008
ComponentsMAP/microtubule affinity-regulating kinase 3
KeywordsTRANSFERASE / Kinase Inhibitor Active site Folded activation loop UBA domain
Function / homology
Function and homology information


peptidyl-serine autophosphorylation / negative regulation of protein localization to nucleus / tau-protein kinase activity / negative regulation of hippo signaling / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / tau protein binding / microtubule cytoskeleton organization / Negative regulation of MAPK pathway ...peptidyl-serine autophosphorylation / negative regulation of protein localization to nucleus / tau-protein kinase activity / negative regulation of hippo signaling / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / tau protein binding / microtubule cytoskeleton organization / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Signaling by BRAF and RAF1 fusions / positive regulation of protein binding / peptidyl-serine phosphorylation / non-specific serine/threonine protein kinase / intracellular signal transduction / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / dendrite / extracellular exosome / ATP binding / plasma membrane / cytoplasm / cytosol
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-V5E / MAP/microtubule affinity-regulating kinase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsDederer, V. / Preuss, F. / Chatterjee, D. / Vlassova, A. / Mathea, S. / Axtman, A. / Knapp, S.
CitationJournal: J.Med.Chem. / Year: 2022
Title: Identification of Pyrimidine-Based Lead Compounds for Understudied Kinases Implicated in Driving Neurodegeneration.
Authors: Drewry, D.H. / Annor-Gyamfi, J.K. / Wells, C.I. / Pickett, J.E. / Dederer, V. / Preuss, F. / Mathea, S. / Axtman, A.D.
History
DepositionJul 1, 2021Deposition site: PDBE / Processing site: PDBE
SupersessionJul 14, 2021ID: 7O94
Revision 1.0Jul 14, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 10, 2021Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_2 / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Feb 9, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.3Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: MAP/microtubule affinity-regulating kinase 3
B: MAP/microtubule affinity-regulating kinase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,5007
Polymers75,3972
Non-polymers1,1035
Water1,856103
1
A: MAP/microtubule affinity-regulating kinase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2814
Polymers37,6991
Non-polymers5823
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: MAP/microtubule affinity-regulating kinase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,2193
Polymers37,6991
Non-polymers5202
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)50.989, 95.733, 68.579
Angle α, β, γ (deg.)90.000, 91.982, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 50 through 51 or (resid 52...
d_2ens_1(chain "B" and ((resid 50 and (name N or name...

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1GLNHISA1 - 3
d_12ens_1GLYTHRA5 - 41
d_13ens_1LEULEUA43 - 165
d_14ens_1GLYGLYA167 - 301
d_21ens_1GLNHISB1 - 3
d_22ens_1GLYTHRB5 - 41
d_23ens_1LEUGLYB43 - 300

NCS oper: (Code: givenMatrix: (-0.38515980021, 0.0540705943794, 0.921264510944), (-0.0446319721646, -0.998205309736, 0.0399267664077), (0.921769990487, -0.0257396666361, 0.38688183493)Vector: -25. ...NCS oper: (Code: given
Matrix: (-0.38515980021, 0.0540705943794, 0.921264510944), (-0.0446319721646, -0.998205309736, 0.0399267664077), (0.921769990487, -0.0257396666361, 0.38688183493)
Vector: -25.4752817018, 48.8811889309, -33.5110075099)

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Components

#1: Protein MAP/microtubule affinity-regulating kinase 3 / C-TAK1 / cTAK1 / Cdc25C-associated protein kinase 1 / ELKL motif kinase 2 / EMK-2 / Protein kinase ...C-TAK1 / cTAK1 / Cdc25C-associated protein kinase 1 / ELKL motif kinase 2 / EMK-2 / Protein kinase STK10 / Ser/Thr protein kinase PAR-1 / Par-1a / Serine/threonine-protein kinase p78


Mass: 37698.586 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MARK3, CTAK1, EMK2 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P27448, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-V5E / 5-Bromo-4-N-[2-(1H-imidazol-5-yl)ethyl]-2-N-[3-(morpholin-4-ylmethyl)phenyl]pyrimidine-2,4-diamine / 5-bromanyl-4-N-[2-(1H-imidazol-5-yl)ethyl]-2-N-[3-(morpholin-4-ylmethyl)phenyl]pyrimidine-2,4-diamine / 57593528


Mass: 458.355 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H24BrN7O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 103 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 44.56 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 0.1 M sodium formate pH 7.0 24% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00002 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 21, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00002 Å / Relative weight: 1
ReflectionResolution: 1.95→47.87 Å / Num. obs: 47368 / % possible obs: 98.72 % / Redundancy: 3.5 % / Biso Wilson estimate: 31.35 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.07939 / Net I/σ(I): 11.8
Reflection shellResolution: 1.95→2.02 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.5428 / Mean I/σ(I) obs: 2.47 / Num. unique obs: 4760 / CC1/2: 0.782 / % possible all: 99.44

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Processing

Software
NameVersionClassification
REFMACv7.1.015refinement
PHENIX1.19.2_4158refinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERv7.1.015phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2QNJ

2qnj


Resolution: 1.95→47.87 Å / SU ML: 0.2658 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 25.1286
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2419 2398 5.06 %
Rwork0.2096 44960 -
obs0.2112 47358 98.73 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 34.18 Å2
Refinement stepCycle: LAST / Resolution: 1.95→47.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4578 0 70 103 4751
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01014735
X-RAY DIFFRACTIONf_angle_d1.05696415
X-RAY DIFFRACTIONf_chiral_restr0.0645741
X-RAY DIFFRACTIONf_plane_restr0.0101858
X-RAY DIFFRACTIONf_dihedral_angle_d5.6054706
Refine LS restraints NCSType: Torsion NCS / Rms dev position: 0.669948373269 Å
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-1.990.38341420.31242641X-RAY DIFFRACTION99.39
1.99-2.030.33191360.27892678X-RAY DIFFRACTION99.5
2.03-2.080.30231350.23992647X-RAY DIFFRACTION99.22
2.08-2.130.26361330.23492641X-RAY DIFFRACTION98.97
2.13-2.190.27931420.23722622X-RAY DIFFRACTION98.71
2.19-2.250.28581450.24382585X-RAY DIFFRACTION97.53
2.25-2.330.28471480.23872595X-RAY DIFFRACTION96.65
2.33-2.410.28981590.22542676X-RAY DIFFRACTION99.93
2.41-2.510.27791440.22072632X-RAY DIFFRACTION99.78
2.51-2.620.23061470.23032656X-RAY DIFFRACTION99.43
2.62-2.760.24631280.22222668X-RAY DIFFRACTION99.25
2.76-2.930.24621520.21822636X-RAY DIFFRACTION99.08
2.93-3.160.27481500.22792636X-RAY DIFFRACTION98.45
3.16-3.480.25681490.21922603X-RAY DIFFRACTION97.38
3.48-3.980.24751470.18972670X-RAY DIFFRACTION99.3
3.98-5.010.15081170.16332691X-RAY DIFFRACTION98.84
5.01-47.870.20471240.18982683X-RAY DIFFRACTION97.13
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)
10.7821592597060.7557845071260.3847522958521.998465232461.329749489611.57736146277-0.0471434556356-0.0111150566988-0.04894226819590.007631294289330.104497484443-0.240804593689-0.03096575351670.1529305817560.003099047548190.237024320729-0.0217984218055-0.01986580803580.2597567579670.03380638823960.278853149990.9387468506499.22235104542-0.701987560389
22.834536603960.400612678227-0.267648669313.419262565260.5258785170471.45910984895-0.0275324614983-0.0189810964713-0.346397859241-0.1930785019510.134929877864-0.4423892300640.2733780608050.15773781625-0.1225720528290.3002384297360.0312252715973-0.04428959948030.252996794131-0.01132684985050.32628020311614.60763957218.49453159498.20764186001
30.8338494432360.9437722744810.7350431627351.643074866471.31870098421.057027095710.180165779977-0.2252932071260.03152774842530.425682022887-0.1760019675450.06049431024810.292812247342-0.196809203347-0.0002119600816030.327764691799-0.0377047538760.002342927323320.3146109194560.04398395178160.230130779134-4.7937244101310.915375824610.48918549
41.8402350843-0.9963064084250.7873739789531.11161144239-0.9206166166761.32328597696-0.014940798058-0.1508525281620.008888814905250.1062231562320.00680482022924-0.0350711968919-0.0693629115853-0.0803854866801-0.01175287916650.24668038541-0.02017565677240.005870539072950.226207745912-0.01377904873590.221975290674-27.097905221540.8844740537-33.5240406895
51.52853021146-0.656953761568-0.2338197043933.43114963733-0.3648867125462.40368765842-0.0470156357129-0.1313344093550.1386876727490.385395631871-0.0641422102886-0.0921492173919-0.03573590505820.05940237023790.101048132030.238018997959-0.016468104302-0.02719197816350.236064124542-0.02098439344320.224323174227-16.668852888428.6728552361-20.7374912398
61.25866048521-1.232907201751.50199041441.22014723329-1.369944608871.82651499756-0.0001970195984730.2992050735210.101406427180.169810691565-0.357018660656-0.405930332402-0.2659425032990.5189702564110.367108061440.274854550344-0.0743052573646-0.002731806353280.3688793214370.06392706645950.364447702438-18.04038048250.8798859521-46.7303811645
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 50 through 194 )AA50 - 1941 - 145
22chain 'A' and (resid 195 through 267 )AA195 - 267146 - 203
33chain 'A' and (resid 268 through 365 )AA268 - 365204 - 301
44chain 'B' and (resid 50 through 172 )BB50 - 1721 - 123
55chain 'B' and (resid 173 through 313 )BB173 - 313124 - 248
66chain 'B' and (resid 314 through 365 )BB314 - 365249 - 300

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