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- PDB-8d6c: Crystal Structure of Human Myt1 Kinase domain Bounded with compound 28 -

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Basic information

Entry
Database: PDB / ID: 8d6c
TitleCrystal Structure of Human Myt1 Kinase domain Bounded with compound 28
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-QGR / Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 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 ...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
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)70,38111
Polymers68,9962
Non-polymers1,3859
Water1629
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A: 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
2
B: Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2376
Polymers34,4981
Non-polymers7395
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.640, 112.730, 72.660
Angle α, β, γ (deg.)90.000, 110.420, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 78 through 107 or (resid 108...
21(chain B and (resid 78 through 79 or (resid 80...

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
11GLNGLNGLNGLN(chain A and (resid 78 through 107 or (resid 108...AA78 - 10727 - 56
12GLNGLNGLNGLN(chain A and (resid 78 through 107 or (resid 108...AA10857
13GLNGLNPROPRO(chain A and (resid 78 through 107 or (resid 108...AA78 - 36227 - 311
14GLNGLNPROPRO(chain A and (resid 78 through 107 or (resid 108...AA78 - 36227 - 311
15GLNGLNPROPRO(chain A and (resid 78 through 107 or (resid 108...AA78 - 36227 - 311
16GLNGLNPROPRO(chain A and (resid 78 through 107 or (resid 108...AA78 - 36227 - 311
21GLNGLNPROPRO(chain B and (resid 78 through 79 or (resid 80...BB78 - 7927 - 28
22ARGARGARGARG(chain B and (resid 78 through 79 or (resid 80...BB8029
23LEULEUARGARG(chain B and (resid 78 through 79 or (resid 80...BB77 - 36026 - 309
24LEULEUARGARG(chain B and (resid 78 through 79 or (resid 80...BB77 - 36026 - 309
25LEULEUARGARG(chain B and (resid 78 through 79 or (resid 80...BB77 - 36026 - 309
26LEULEUARGARG(chain B and (resid 78 through 79 or (resid 80...BB77 - 36026 - 309

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Components

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Protein , 1 types, 2 molecules AB

#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, 18 molecules

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


Mass: 62.068 Da / Num. of mol.: 4 / 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-QGR / (1P)-2-amino-6-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: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 9 / 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: 2.87 Å3/Da / Density % sol: 57.18 %
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: Dec 5, 2021
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.19→58.29 Å / Num. obs: 39393 / % possible obs: 98.7 % / Redundancy: 3.506 % / Biso Wilson estimate: 66.71 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.071 / Rrim(I) all: 0.084 / Χ2: 0.726 / Net I/σ(I): 7.38 / Num. measured all: 138123
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
2.19-2.333.5731.60.5522363642362590.5541.87797.4
2.33-2.493.5790.8421.0921464603659980.7770.98999.4
2.49-2.693.4270.4541.9819191562656000.920.53999.5
2.69-2.943.4810.2273.8117762517651020.9780.26898.6
2.94-3.293.6080.1087.9416835468946660.9930.12799.5
3.29-3.83.4750.06613.9414226414440940.9950.07898.8
3.8-4.643.3940.05718.911739352234590.9940.06898.2
4.64-6.553.5180.05521.239541274427120.9950.06598.8
6.55-58.293.3280.05322.145002154115030.9940.06397.5

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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: 2.2→58.29 Å / SU ML: 0.47 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 42.73 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2674 1963 5.03 %
Rwork0.2414 37060 -
obs0.2426 39023 98.19 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 223.53 Å2 / Biso mean: 99.7787 Å2 / Biso min: 54.31 Å2
Refinement stepCycle: final / Resolution: 2.2→58.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4130 0 86 9 4225
Biso mean--92.05 81.27 -
Num. residues----555
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2424X-RAY DIFFRACTION6.499TORSIONAL
12B2424X-RAY DIFFRACTION6.499TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.2-2.250.67281250.62992382250788
2.25-2.310.54141370.51172635277299
2.31-2.380.471350.47262658279399
2.38-2.460.48931440.45492695283999
2.46-2.540.47651370.432326542791100
2.54-2.650.43461630.39022646280999
2.65-2.770.40971440.34512638278298
2.77-2.910.32851420.30012664280699
2.91-3.10.34091420.291426612803100
3.1-3.330.3461670.269326742841100
3.33-3.670.31291160.23262713282999
3.67-4.20.2181250.20452633275898
4.2-5.290.16541450.18352687283299
5.29-58.290.21591410.19122720286198
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)
10.92830.25680.72950.95491.28882.8604-0.06650.00910.4584-0.4317-0.71850.3911-0.5955-0.3944-0.06890.71310.1423-0.32960.9109-0.17271.395846.3115-10.49220.9173
21.55641.21471.2171.63040.43973.0373-0.2741-0.19130.2329-0.3727-0.27330.14650.2330.2252-0.39050.60230.0091-0.10810.871-0.09050.98251.3302-18.77853.4232
30.85730.35221.1923.28272.11292.142-0.1736-0.15480.18870.5492-0.05380.4369-0.13520.1272-0.00010.6513-0.00450.06630.6938-0.00780.703858.4071-14.875118.0973
40.79220.10620.3931.01960.43750.627-0.1274-0.0415-0.0281-0.2142-0.0863-0.10150.30230.2877-0.00010.89060.0711-0.02110.77670.03570.700467.8291-26.107816.1418
50.5353-0.6095-0.36511.28820.78790.46940.1003-0.175-0.24890.9563-0.0306-0.63770.63250.12840.00011.04520.0807-0.12780.8339-0.01370.823477.5581-22.543725.4137
60.1052-0.02450.15110.0044-0.02850.22570.25980.75340.70630.79350.27730.1711-0.8264-1.56590.00121.5676-0.00740.00250.97630.07010.952661.7914-21.485535.739
72.64881.1075-1.23721.53981.36263.7395-0.63320.4613-0.2809-0.4492-0.0013-0.40990.71280.3385-0.00020.98630.11060.22080.8150.04221.094880.48359.034-2.604
80.921.3415-0.23811.9535-0.17810.5194-0.2327-0.1606-0.3268-0.696-0.2179-0.81890.23550.3877-0.00040.76970.08050.02990.90780.12520.951778.507717.67823.9803
91.7239-0.53530.17752.8381-0.64471.11340.1612-0.0690.07050.4691-0.0054-0.0204-0.4-0.032700.8493-0.01430.01360.7350.02350.650962.645317.738216.4453
101.11110.1611-1.23071.8213-0.09731.42690.4883-0.83820.15821.9773-0.24890.7684-1.30710.01530.03661.4416-0.09310.17450.9959-0.05740.822856.540321.449428.0267
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 78 through 129 )A78 - 129
2X-RAY DIFFRACTION2chain 'A' and (resid 130 through 164 )A130 - 164
3X-RAY DIFFRACTION3chain 'A' and (resid 165 through 249 )A165 - 249
4X-RAY DIFFRACTION4chain 'A' and (resid 250 through 301 )A250 - 301
5X-RAY DIFFRACTION5chain 'A' and (resid 302 through 349 )A302 - 349
6X-RAY DIFFRACTION6chain 'A' and (resid 350 through 362 )A350 - 362
7X-RAY DIFFRACTION7chain 'B' and (resid 77 through 147 )B77 - 147
8X-RAY DIFFRACTION8chain 'B' and (resid 148 through 188 )B148 - 188
9X-RAY DIFFRACTION9chain 'B' and (resid 189 through 316 )B189 - 316
10X-RAY DIFFRACTION10chain 'B' and (resid 317 through 360 )B317 - 360

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