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- PDB-8d6d: Crystal Structure of Human Myt1 Kinase domain Bounded with compound 39 -

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Basic information

Entry
Database: PDB / ID: 8d6d
TitleCrystal Structure of Human Myt1 Kinase domain Bounded with compound 39
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-QGY / Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 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.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 / _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 / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)70,35111
Polymers68,9962
Non-polymers1,3559
Water59433
1
A: Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2076
Polymers34,4981
Non-polymers7095
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1455
Polymers34,4981
Non-polymers6464
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.460, 112.920, 72.660
Angle α, β, γ (deg.)90.000, 110.340, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 78 through 84 or resid 95...
21(chain B and (resid 78 through 79 or (resid 80...

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain A and (resid 78 through 84 or resid 95...A78 - 84
121(chain A and (resid 78 through 84 or resid 95...A95 - 107
131(chain A and (resid 78 through 84 or resid 95...A108 - 109
141(chain A and (resid 78 through 84 or resid 95...A78 - 361
151(chain A and (resid 78 through 84 or resid 95...A1
211(chain B and (resid 78 through 79 or (resid 80...B78 - 79
221(chain B and (resid 78 through 79 or (resid 80...B80
231(chain B and (resid 78 through 79 or (resid 80...B77 - 361
241(chain B and (resid 78 through 79 or (resid 80...B77 - 361
251(chain B and (resid 78 through 79 or (resid 80...B77 - 361
261(chain B and (resid 78 through 79 or (resid 80...B77 - 361

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Components

#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
#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 426.267 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H16BrN5O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 33 / 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: 2.87 Å3/Da / Density % sol: 57.13 %
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 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: 0.9791 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: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.35→58.33 Å / Num. obs: 30950 / % possible obs: 94.8 % / Redundancy: 2.651 % / Biso Wilson estimate: 77.15 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.064 / Rrim(I) all: 0.08 / Χ2: 0.712 / Net I/σ(I): 6.95 / Num. measured all: 82045
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
2.35-2.492.5421.3940.5312400522348790.5041.7593.4
2.49-2.662.6450.7561.0812563490947500.7630.94396.8
2.66-2.872.7650.3962.112486464345160.9460.49297.3
2.87-3.142.7240.1964.1311082423440680.9750.24496.1
3.14-3.512.6180.0928.239523383936380.990.11594.8
3.51-4.062.5510.0613.218070340831640.9940.07492.8
4.06-4.962.7280.05417.687379288127050.9930.06793.9
4.96-6.992.6040.05218.225349223420540.9910.06591.9
6.99-58.332.7150.04720.383193128611760.9920.05891.4

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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: 2.35→58.33 Å / SU ML: 0.54 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 41.47 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2719 1533 4.99 %
Rwork0.2406 29186 -
obs0.2422 30719 94.79 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 215.83 Å2 / Biso mean: 106.0445 Å2 / Biso min: 57.7 Å2
Refinement stepCycle: final / Resolution: 2.35→58.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3993 0 84 33 4110
Biso mean--97.46 101.99 -
Num. residues----544
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2338X-RAY DIFFRACTION6.757TORSIONAL
12B2338X-RAY DIFFRACTION6.757TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.35-2.430.52911480.55832585273394
2.43-2.510.54721450.49642620276595
2.51-2.610.44761380.42752697283597
2.61-2.730.41311270.39892733286097
2.73-2.880.48011530.40682694284797
2.88-3.060.40311590.3492667282696
3.06-3.290.31161390.27692659279896
3.29-3.620.2751260.26942632275893
3.62-4.150.24781310.20992623275494
4.15-5.220.21411640.18512614277893
5.23-58.330.2211030.19242662276592
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)
10.8217-0.20051.77521.7851.6022.1427-0.3128-0.01160.2885-0.5783-0.63380.5286-0.1768-0.1473-0.0010.58680.0278-0.1020.7477-0.10451.20149.1203-12.43373.6918
20.4418-0.44031.02440.67810.14330.2211-0.3691-0.05010.28550.3190.0340.46750.27370.1454-0.00020.8902-0.03680.0360.72590.02390.681262.3197-12.253921.8495
35.19830.3202-0.451.042-0.30170.3221-0.61090.7654-0.481-0.02020.47470.33120.6160.2648-0.10720.9852-0.0111-0.05140.9216-0.00710.743966.4106-26.581612.7293
40.2038-0.1254-0.32280.24340.2050.1333-0.0701-0.0995-0.20260.48660.1724-0.33010.04040.18650.00010.62880.1288-0.06280.7766-0.03460.666175.3243-18.715219.8606
50.05080.02680.10640.0473-0.03870.11380.4007-0.52770.73230.4161-0.4571-0.0680.96730.0484-0.00111.24440.2031-0.16491.19590.0571.401381.6098-15.657528.4928
60.11430.42130.40480.09210.21850.15810.46470.02730.1661.2851-0.1925-0.22650.80180.0985-0.00011.41280.00910.0260.88920.00450.76669.1449-23.097131.7851
70.2127-0.030.17850.0513-0.05280.1437-0.33210.02670.9059-0.1021-0.5826-0.31330.88690.2461-0.00191.06170.05170.3581.18110.15031.562487.991815.2352-6.448
80.59030.1926-0.80370.4965-0.00120.9738-0.53550.2613-0.4621-1.2001-0.2343-0.36760.4651-0.1089-0.00520.94270.080.230.7208-0.04561.009675.988713.4136-0.4768
90.6462-0.05090.52581.8635-1.00961.22190.0067-0.2239-0.24290.1271-0.1441-0.43470.1839-0.02050.00550.6299-0.0238-0.03480.6931-0.00370.718970.043614.789715.0051
101.9661.8448-1.09646.5558-0.96931.40440.42480.20250.4187-0.49580.05121.1105-0.1229-0.79440.5150.7140.0740.08860.703-0.00760.653967.788527.35788.3184
115.78020.2991-0.31993.67253.57438.34711.17370.381.97390.01021.7437-0.7361-4.13051.14850.89260.2970.4498-0.49230.50860.2175-0.142456.893730.228612.3443
120.1389-0.1634-0.06730.118-0.0644-0.00840.34270.07350.6603-0.0266-0.08520.16920.7658-0.10370.00021.05540.0650.07930.9967-0.04380.902458.584420.928219.7292
132.54351.66781.47984.2684-1.59123.48240.5521-0.57940.6880.6817-0.11830.8471-0.4844-1.3695-1.7090.7053-0.00370.1241.09020.11061.132347.760120.687619.7342
140.65350.4663-0.22280.8425-0.27350.40570.888-1.21830.78941.6988-0.32720.597-1.5314-0.21280.01331.8434-0.12210.1041.3196-0.05490.739760.243825.322729.1056
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 78 through 188 )A78 - 188
2X-RAY DIFFRACTION2chain 'A' and (resid 189 through 249 )A189 - 249
3X-RAY DIFFRACTION3chain 'A' and (resid 250 through 284 )A250 - 284
4X-RAY DIFFRACTION4chain 'A' and (resid 285 through 316 )A285 - 316
5X-RAY DIFFRACTION5chain 'A' and (resid 317 through 329 )A317 - 329
6X-RAY DIFFRACTION6chain 'A' and (resid 330 through 361 )A330 - 361
7X-RAY DIFFRACTION7chain 'B' and (resid 77 through 104 )B77 - 104
8X-RAY DIFFRACTION8chain 'B' and (resid 105 through 164 )B105 - 164
9X-RAY DIFFRACTION9chain 'B' and (resid 165 through 249 )B165 - 249
10X-RAY DIFFRACTION10chain 'B' and (resid 250 through 270 )B250 - 270
11X-RAY DIFFRACTION11chain 'B' and (resid 271 through 284 )B271 - 284
12X-RAY DIFFRACTION12chain 'B' and (resid 285 through 301 )B285 - 301
13X-RAY DIFFRACTION13chain 'B' and (resid 302 through 329 )B302 - 329
14X-RAY DIFFRACTION14chain 'B' and (resid 330 through 361 )B330 - 361

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