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- PDB-9lid: Crystal structure of human PKMYT1 protein kinase domain with Naph... -

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Basic information

Entry
Database: PDB / ID: 9lid
TitleCrystal structure of human PKMYT1 protein kinase domain with Naphthyridinone Inhibitor compound 27
ComponentsMembrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
KeywordsTRANSFERASE / inhibitor
Function / homology
Function and homology information


negative regulation of G2/MI transition of meiotic cell cycle / G2/M DNA replication checkpoint / negative regulation of G2/M transition of mitotic cell cycle / Polo-like kinase mediated events / regulation of cyclin-dependent protein serine/threonine kinase activity / regulation of mitotic nuclear division / Cyclin A/B1/B2 associated events during G2/M transition / meiotic cell cycle / G2/M transition of mitotic cell cycle / kinase activity ...negative regulation of G2/MI transition of meiotic cell cycle / G2/M DNA replication checkpoint / negative regulation of G2/M transition of mitotic cell cycle / Polo-like kinase mediated events / regulation of cyclin-dependent protein serine/threonine kinase activity / regulation of mitotic nuclear division / Cyclin A/B1/B2 associated events during G2/M transition / meiotic cell cycle / G2/M transition of mitotic cell cycle / kinase activity / mitotic cell cycle / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / protein kinase activity / Golgi membrane / protein serine kinase activity / protein serine/threonine kinase activity / endoplasmic reticulum membrane / nucleolus / endoplasmic reticulum / Golgi apparatus / nucleoplasm / ATP binding / metal ion binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
Tyrosine/threonine-protein kinase, Cdc2 inhibitor / : / 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
: / Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.06 Å
AuthorsXu, Z.H. / Chen, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of Naphthyridinone Derivatives as Selective and Potent PKMYT1 Inhibitors with Antitumor Efficacy.
Authors: Chen, B. / Liu, X. / Mu, T. / Xu, J. / Zhao, D. / Dey, F. / Tang, Y. / Xu, Z. / Yang, J. / Huang, K. / Li, C. / Chen, S. / Zhu, S. / Wang, S. / Yao, X. / Yan, Z. / Tu, Y. / Dai, Y. / Qiu, H. ...Authors: Chen, B. / Liu, X. / Mu, T. / Xu, J. / Zhao, D. / Dey, F. / Tang, Y. / Xu, Z. / Yang, J. / Huang, K. / Li, C. / Chen, S. / Zhu, S. / Wang, S. / Yao, X. / Yan, Z. / Tu, Y. / Dai, Y. / Qiu, H. / Yang, J. / Jiang, T. / Qi, Y. / Li, Y. / Shen, H.C. / Zhu, W. / Tan, X. / Wu, J.
History
DepositionJan 14, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0May 14, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
B: Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,46214
Polymers63,6162
Non-polymers1,84612
Water2,000111
1
A: Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8278
Polymers31,8081
Non-polymers1,0197
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area380 Å2
ΔGint-29 kcal/mol
Surface area13810 Å2
MethodPISA
2
B: Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6356
Polymers31,8081
Non-polymers8275
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area400 Å2
ΔGint-29 kcal/mol
Surface area14040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.484, 112.359, 72.390
Angle α, β, γ (deg.)90.00, 110.33, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase / Myt1 kinase


Mass: 31808.197 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Strain: Homo sapiens / Gene: PKMYT1, MYT1 / Variant: 9606 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / Variant (production host): Escherichia coli
References: UniProt: Q99640, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-A1EJX / 4-[7-azanyl-8-(7-fluoranyl-1H-indazol-4-yl)-6-oxidanylidene-5H-1,5-naphthyridin-3-yl]-N,N-dimethyl-benzamide


Mass: 442.445 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H19FN6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 10 / Source method: isolated from a natural source / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 111 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 3.03 Å3/Da / Density % sol: 59.36 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 6.9 MG/ML MYT1, 25 mM HEPES, 100 MM SODIUM CHLORIDE, 0.5 mM DTT, 0.1 M CALCIUM CHLORIDE, 0.05 M TRIS pH 8.5, 10 % PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.9793 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 26, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.06→68.027 Å / Num. obs: 28634 / % possible obs: 99 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.059 / Rpim(I) all: 0.038 / Rrim(I) all: 0.076 / Net I/σ(I): 10
Reflection shellResolution: 2.06→2.117 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.798 / Num. unique obs: 264 / Rpim(I) all: 0.496 / Rrim(I) all: 0.941 / % possible all: 59.5

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Processing

Software
NameVersionClassification
PHENIX(1.21.2_5419: ???)refinement
Aimlessdata scaling
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.06→32.3 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 35.85 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2307 1484 5.18 %
Rwork0.2032 --
obs0.2046 28634 61.57 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.06→32.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4295 0 116 111 4522
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0044510
X-RAY DIFFRACTIONf_angle_d0.6376112
X-RAY DIFFRACTIONf_dihedral_angle_d12.2151720
X-RAY DIFFRACTIONf_chiral_restr0.04626
X-RAY DIFFRACTIONf_plane_restr0.005799
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.40.3303530.326905X-RAY DIFFRACTION23
2.4-2.530.34621070.32371984X-RAY DIFFRACTION50
2.53-2.680.33022000.30863367X-RAY DIFFRACTION85
2.68-2.890.33612060.2933978X-RAY DIFFRACTION100
2.89-3.180.30762250.26583985X-RAY DIFFRACTION100
3.18-3.640.22722150.20663988X-RAY DIFFRACTION99
3.64-4.590.19832040.16393969X-RAY DIFFRACTION98
4.59-100.18622210.16364001X-RAY DIFFRACTION99
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)
14.19011.2243-0.04598.38522.63913.2666-0.0641-0.24390.16291.3680.5684-1.9022-0.35942.0686-0.4640.9006-0.1016-0.40740.90210.00921.374923.284712.510239.9245
21.99661.11340.66311.1232-1.00174.2674-0.0224-0.42110.74621.7991-0.5286-0.2965-1.7942-0.13530.54271.0923-0.0159-0.41310.3092-0.10061.120811.453320.762534.663
32.15590.82792.17886.0701-0.77894.763-0.24530.1640.55060.50290.0372-0.3409-0.9218-0.03840.11670.34010.0071-0.07570.2755-0.02590.545712.27928.533533.6442
43.5451-0.51571.39976.1643-1.54784.606-0.15230.76230.1478-0.3399-0.009-0.7875-0.45920.39130.09910.3167-0.02930.10740.3917-0.04160.37946.270812.727419.2365
54.55151.9378-0.62588.9476-0.06673.0943-0.04280.1614-0.269-0.00040.2-0.14450.2327-0.2676-0.16710.30860.02470.02180.3772-0.05080.201-1.284.149519.8553
63.33132.6204-0.81766.4278-4.44725.01120.07410.3720.3497-0.49410.79691.7862-0.3618-1.7386-0.88850.57720.0458-0.14440.94530.19650.8621-17.32046.829815.0391
74.9914-1.16111.21877.0903-1.73825.5910.05590.78740.0531-2.05860.17710.04630.3234-0.1412-0.27360.9043-0.0721-0.06840.7939-0.08360.3344-4.51131.94164.8068
82.13881.184-1.06845.90843.3065.6062-0.1736-0.3737-1.00990.9665-0.44850.47810.6547-0.52860.42610.4872-0.06280.10480.39690.1331.3181-16.718135.550532.8445
91.8994-0.3996-1.5793.36960.81383.7431-0.10130.2124-0.1613-0.5779-0.1390.8117-0.0833-0.28050.21690.31290.0084-0.14740.28540.0340.4088-6.724841.436618.011
109.5763-5.81333.96733.8107-3.4366.5754-0.7037-0.45341.29731.13840.4018-0.2678-1.5024-0.36390.28120.69450.0294-0.00370.4461-0.03490.7363-3.921155.303323.0191
113.5006-0.93580.97785.1032-0.07235.8235-0.18480.30030.1035-1.08040.1682-0.48580.04040.61660.05620.6021-0.06510.05320.45770.08090.27389.375748.149.6057
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 77 through 104 )
2X-RAY DIFFRACTION2chain 'A' and (resid 105 through 129 )
3X-RAY DIFFRACTION3chain 'A' and (resid 130 through 164 )
4X-RAY DIFFRACTION4chain 'A' and (resid 165 through 227 )
5X-RAY DIFFRACTION5chain 'A' and (resid 228 through 301 )
6X-RAY DIFFRACTION6chain 'A' and (resid 302 through 329 )
7X-RAY DIFFRACTION7chain 'A' and (resid 330 through 361 )
8X-RAY DIFFRACTION8chain 'B' and (resid 77 through 147 )
9X-RAY DIFFRACTION9chain 'B' and (resid 148 through 249 )
10X-RAY DIFFRACTION10chain 'B' and (resid 250 through 269 )
11X-RAY DIFFRACTION11chain 'B' and (resid 270 through 361 )

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