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- PDB-8d6e: Crystal Structure of Human Myt1 Kinase domain Bounded with RP-6306 -

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Basic information

Entry
Database: PDB / ID: 8d6e
TitleCrystal Structure of Human Myt1 Kinase domain Bounded with RP-6306
ComponentsMembrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
KeywordsSIGNALING PROTEIN / Transferase/Inhibitor / Kinase Inhibitor complex / Transferase-Inhibitor complex
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 mitotic nuclear division / regulation of cyclin-dependent protein serine/threonine kinase activity / 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 mitotic nuclear division / regulation of cyclin-dependent protein serine/threonine kinase activity / 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 / non-specific serine/threonine protein kinase / protein kinase activity / Golgi membrane / protein serine kinase activity / protein serine/threonine kinase activity / endoplasmic reticulum membrane / nucleolus / Golgi apparatus / endoplasmic reticulum / nucleoplasm / ATP binding / membrane / nucleus / metal ion binding / 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
Chem-QGI / Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsPau, V.P.T. / Mao, D.Y.L. / Mader, P. / Orlicky, S. / Sicheri, F.
Funding support Canada, 2items
OrganizationGrant numberCountry
Ontario Research FundRE08-065 Canada
Other private
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306.
Authors: Szychowski, J. / Papp, R. / Dietrich, E. / Liu, B. / Vallee, F. / Leclaire, M.E. / Fourtounis, J. / Martino, G. / Perryman, A.L. / Pau, V. / Yin, S.Y. / Mader, P. / Roulston, A. / Truchon, J. ...Authors: Szychowski, J. / Papp, R. / Dietrich, E. / Liu, B. / Vallee, F. / Leclaire, M.E. / Fourtounis, J. / Martino, G. / Perryman, A.L. / Pau, V. / Yin, S.Y. / Mader, P. / Roulston, A. / Truchon, J.F. / Marshall, C.G. / Diallo, M. / Duffy, N.M. / Stocco, R. / Godbout, C. / Bonneau-Fortin, A. / Kryczka, R. / Bhaskaran, V. / Mao, D. / Orlicky, S. / Beaulieu, P. / Turcotte, P. / Kurinov, I. / Sicheri, F. / Mamane, Y. / Gallant, M. / Black, W.C.
History
DepositionJun 6, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 27, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 10, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Aug 24, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)70,85821
Polymers68,9962
Non-polymers1,86219
Water1,69394
1
B: Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,50511
Polymers34,4981
Non-polymers1,00710
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
A: Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,35310
Polymers34,4981
Non-polymers8559
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.243, 112.014, 72.978
Angle α, β, γ (deg.)90.000, 109.870, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 77 through 165 or (resid 166...
21(chain B and ((resid 77 through 78 and (name N...

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11LEULEUGLYGLY(chain A and (resid 77 through 165 or (resid 166...AB77 - 16526 - 114
12GLNGLNGLNGLN(chain A and (resid 77 through 165 or (resid 166...AB166115
13LEULEUGLNGLN(chain A and (resid 77 through 165 or (resid 166...AB77 - 36126 - 310
14LEULEUGLNGLN(chain A and (resid 77 through 165 or (resid 166...AB77 - 36126 - 310
15LEULEUGLNGLN(chain A and (resid 77 through 165 or (resid 166...AB77 - 36126 - 310
16LEULEUGLNGLN(chain A and (resid 77 through 165 or (resid 166...AB77 - 36126 - 310
17LEULEUGLNGLN(chain A and (resid 77 through 165 or (resid 166...AB77 - 36126 - 310
21LEULEUGLNGLN(chain B and ((resid 77 through 78 and (name N...BA77 - 7826 - 27
22LEULEUGLNGLN(chain B and ((resid 77 through 78 and (name N...BA77 - 36126 - 310
23LEULEUGLNGLN(chain B and ((resid 77 through 78 and (name N...BA77 - 36126 - 310
24LEULEUGLNGLN(chain B and ((resid 77 through 78 and (name N...BA77 - 36126 - 310
25LEULEUGLNGLN(chain B and ((resid 77 through 78 and (name N...BA77 - 36126 - 310

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Components

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Protein , 1 types, 2 molecules BA

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


Mass: 34498.133 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN, UNP RESIDUES 75-362
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PKMYT1, MYT1 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli)
References: UniProt: Q99640, non-specific serine/threonine protein kinase

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Non-polymers , 5 types, 113 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-QGI / (1P)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide


Mass: 324.377 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H20N4O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 94 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.78 Å3/Da / Density % sol: 55.8 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.25
Details: 5.6 to 6.6% PEG3350, 0.2 M Na2SO4, 0.1 M Tris-HCl and 10% EG
Temp details: 277K for 1 day and then 293K for a week

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 3, 2020
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.15→47.82 Å / Num. obs: 40791 / % possible obs: 86.6 % / Redundancy: 1.997 % / Biso Wilson estimate: 72.702 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.021 / Rrim(I) all: 0.029 / Χ2: 0.872 / Net I/σ(I): 16.97 / Num. measured all: 144392
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.15-2.282.0811.0320.752356313449113240.3561.40884.2
2.28-2.432.0230.4841.572214112732109460.7090.66186
2.43-2.631.9620.243.211972711765100560.9130.32885.5
2.63-2.882.0660.1127.04197591084895650.980.15488.2
2.88-3.222.0050.05114.817283983586200.9950.0787.6
3.22-3.711.8790.02330.5813903867573980.9990.03185.3
3.71-4.541.9920.01448.5913044733365480.9990.01989.3
4.54-6.391.9220.01353.019748570550730.9990.01988.9
6.39-47.821.8950.0158.145224317727570.9990.01486.8

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHENIX1.19.2refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3P1A

3p1a


Resolution: 2.15→47.82 Å / SU ML: 0.32 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 28.09 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2177 2036 4.99 %
Rwork0.19 38735 -
obs0.1915 40771 96.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 208.81 Å2 / Biso mean: 89.4569 Å2 / Biso min: 48.31 Å2
Refinement stepCycle: final / Resolution: 2.15→47.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4178 0 124 94 4396
Biso mean--87.49 78.69 -
Num. residues----559
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2462X-RAY DIFFRACTION6.229TORSIONAL
12B2462X-RAY DIFFRACTION6.229TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.15-2.20.37131260.34932431255792
2.2-2.250.36471370.33332577271497
2.25-2.310.3361360.29772605274197
2.31-2.380.30511360.27292566270297
2.38-2.460.30141330.262611274497
2.46-2.550.2821330.23852482261594
2.55-2.650.26931350.21972583271897
2.65-2.770.26381370.21232603274097
2.77-2.910.24581410.23042644278598
2.91-3.10.27371340.23912582271697
3.1-3.330.2331410.21572625276698
3.34-3.670.2441330.19872548268195
3.67-4.20.2261370.1692619275698
4.2-5.290.17991380.1622642278098
5.29-47.820.16711390.16162617275695
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)
10.235-0.2256-0.38541.08661.58152.3109-0.33630.090.00720.2929-0.6760.4095-0.1311-1.0479-1.29980.64170.0526-0.35921.1179-0.21671.3509-11.807-17.6179-0.5879
20.2538-0.10020.45780.129-0.26140.9228-0.67580.06860.4508-1.1865-0.3221.5373-1.0533-0.3259-0.75040.97260.1392-0.54690.6276-0.15261.4742-0.145-6.15642.9604
31.73811.4620.70721.22980.35742.56-0.3227-0.17350.2653-0.2814-0.33150.5777-0.3048-0.222-0.89130.60070.0149-0.13490.6699-0.08980.8096-0.1763-18.58723.7125
40.266-0.08040.6782.85180.88271.6439-0.0975-0.2340.15220.7452-0.34280.78930.1623-0.2863-0.01060.6608-0.04090.07350.6523-0.09680.67616.9456-14.765318.6006
52.09970.04821.49280.9865-1.21162.8066-0.00680.4936-0.5980.0662-0.15030.09261.1396-0.40840.25591.0653-0.09040.02010.6477-0.07870.92128.4124-30.37311.1608
60.4612-0.28850.0620.2785-0.13080.0819-0.21910.19760.07390.60050.1082-0.28240.39150.208500.91810.0233-0.02180.69770.02030.568720.009-24.584418.6883
70.4940.0171-0.29010.4136-0.0040.16710.1204-0.15330.01560.41640.0698-1.16370.02510.6083-0.00250.88010.048-0.15020.7658-0.02780.775529.7322-19.34222.0883
80.99011.02590.13621.44870.63210.81660.0685-0.4277-0.35191.3792-0.0821-0.63580.45060.4469-0.00731.2579-0.03740.03960.7493-0.00320.554917.9739-24.991132.1132
92.10620.72232.04540.25310.71822.0016-0.79160.5631-0.4137-0.793-0.7827-0.5961.24530.9003-3.33511.44630.46570.93231.04920.33511.472435.924812.4968-4.632
102.2632-0.94080.60910.4561-0.39866.0761-0.72880.2362-0.1031-1.6116-0.5892-1.31241.2962-0.3188-4.66761.20170.22840.50050.44020.10541.047124.31354.82711.8471
110.34480.5960.52333.8641-1.52112.7879-0.4905-0.3502-0.4401-1.39040.1698-0.20851.0274-0.3005-0.28070.72730.01060.12190.73980.02520.711823.104522.0236-1.1939
121.23090.7884-2.07291.2094-0.60014.1411-0.45-0.5432-0.6425-0.8792-0.5057-1.65170.07551.43070.09590.82160.18040.30650.86150.23340.992228.102814.19836.2143
131.3012-0.79680.17822.70230.4070.94690.14780.0345-0.12050.0478-0.1617-0.06860.09-0.08310.00010.61170.0318-0.02320.64140.03960.557315.051615.380516.7832
141.75540.3581-0.1570.15230.26211.308-0.29530.12190.37630.01320.47220.2435-1.0815-0.47040.15880.85920.1077-0.04630.74070.01490.6155.043928.23712.2747
150.4297-0.4204-0.25360.46360.34480.37970.24050.2226-0.15450.0828-0.08260.3610.2427-0.2553-0.00040.6210.07450.06120.79710.06770.6160.811519.940718.2396
160.7756-1.47840.22824.3032-1.83361.3716-0.1878-0.2458-0.36611.44510.6090.8670.0783-0.6870.19781.0968-0.04660.24420.96640.1650.7550.298316.647229.399
171.0166-0.3940.38841.6756-1.14331.0248-0.0994-0.58780.49111.5732-0.27320.3027-0.4653-0.036-0.05641.0197-0.002-0.02160.80490.04090.519611.22325.432729.0817
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'B' and (resid 77 through 104 )B77 - 104
2X-RAY DIFFRACTION2chain 'B' and (resid 105 through 129 )B105 - 129
3X-RAY DIFFRACTION3chain 'B' and (resid 130 through 164 )B130 - 164
4X-RAY DIFFRACTION4chain 'B' and (resid 165 through 249 )B165 - 249
5X-RAY DIFFRACTION5chain 'B' and (resid 250 through 269 )B250 - 269
6X-RAY DIFFRACTION6chain 'B' and (resid 270 through 301 )B270 - 301
7X-RAY DIFFRACTION7chain 'B' and (resid 302 through 329 )B302 - 329
8X-RAY DIFFRACTION8chain 'B' and (resid 330 through 361 )B330 - 361
9X-RAY DIFFRACTION9chain 'A' and (resid 77 through 109 )A77 - 109
10X-RAY DIFFRACTION10chain 'A' and (resid 110 through 140 )A110 - 140
11X-RAY DIFFRACTION11chain 'A' and (resid 141 through 164 )A141 - 164
12X-RAY DIFFRACTION12chain 'A' and (resid 165 through 188 )A165 - 188
13X-RAY DIFFRACTION13chain 'A' and (resid 189 through 270 )A189 - 270
14X-RAY DIFFRACTION14chain 'A' and (resid 271 through 284 )A271 - 284
15X-RAY DIFFRACTION15chain 'A' and (resid 285 through 321 )A285 - 321
16X-RAY DIFFRACTION16chain 'A' and (resid 322 through 339 )A322 - 339
17X-RAY DIFFRACTION17chain 'A' and (resid 340 through 361 )A340 - 361

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