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- PDB-8d6f: Crystal Structure of Human Myt1 Kinase domain Bounded with Eph re... -

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Basic information

Entry
Database: PDB / ID: 8d6f
TitleCrystal Structure of Human Myt1 Kinase domain Bounded with Eph receptor inhibitor / compound 41
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 / protein tyrosine kinase activity / non-specific serine/threonine protein kinase / protein kinase activity / phosphorylation / 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 / cytoplasm / cytosol
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-QG5 / Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.49 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
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)69,8556
Polymers68,9962
Non-polymers8594
Water39622
1
B: Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9283
Polymers34,4981
Non-polymers4292
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)34,9283
Polymers34,4981
Non-polymers4292
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)50.748, 112.047, 72.506
Angle α, β, γ (deg.)90.000, 110.210, 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 94...
21(chain B and ((resid 78 and (name N or name...

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
11GLNGLNPHEPHE(chain A and (resid 78 through 84 or resid 94...AB78 - 8427 - 33
12SERSERGLNGLN(chain A and (resid 78 through 84 or resid 94...AB94 - 10743 - 56
13GLNGLNGLNGLN(chain A and (resid 78 through 84 or resid 94...AB10857
14GLNGLNGLNGLN(chain A and (resid 78 through 84 or resid 94...AB78 - 36127 - 310
15GLNGLNGLNGLN(chain A and (resid 78 through 84 or resid 94...AB78 - 36127 - 310
16GLNGLNGLNGLN(chain A and (resid 78 through 84 or resid 94...AB78 - 36127 - 310
17GLNGLNGLNGLN(chain A and (resid 78 through 84 or resid 94...AB78 - 36127 - 310
21GLNGLNGLNGLN(chain B and ((resid 78 and (name N or name...BA7827
22GLNGLNGLNGLN(chain B and ((resid 78 and (name N or name...BA76 - 36125 - 310
23GLNGLNGLNGLN(chain B and ((resid 78 and (name N or name...BA76 - 36125 - 310
24GLNGLNGLNGLN(chain B and ((resid 78 and (name N or name...BA76 - 36125 - 310
25GLNGLNGLNGLN(chain B and ((resid 78 and (name N or name...BA76 - 36125 - 310

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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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-QG5 / (1M)-2-amino-1-(5-hydroxy-2-methylphenyl)-1H-pyrrolo[2,3-b]quinoxaline-3-carboxamide


Mass: 333.344 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H15N5O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 22 / 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: 2.8 Å3/Da / Density % sol: 56.13 %
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: Oct 21, 2017
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.49→68.04 Å / Num. obs: 26430 / % possible obs: 82 % / Redundancy: 1.066 % / Biso Wilson estimate: 73.96 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.053 / Rrim(I) all: 0.075 / Χ2: 1.046 / Net I/σ(I): 6.08 / Num. measured all: 91995
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
2.49-2.641.0860.5320.711414516922130200.6180.75276.9
2.64-2.821.0850.2431.371448716102133510.9230.34382.9
2.82-3.051.0760.1352.441297614846120600.9770.19281.2
3.05-3.341.0710.0634.91181213726110320.9930.08980.4
3.34-3.731.0630.058.191113712318104740.9920.0785
3.73-4.311.0550.04711.1493201096288360.9880.06780.6
4.31-5.271.0450.03712.738392917880290.9940.05387.5
5.27-7.451.0340.03513.056212716460080.9960.0583.9
7.45-68.041.0190.0414.113514392834500.9940.05687.8

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Processing

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

3p1a


Resolution: 2.49→68.04 Å / SU ML: 0.5 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 30.58 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2395 1330 5.03 %
Rwork0.2147 25087 -
obs0.216 26417 98.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 185.06 Å2 / Biso mean: 84.9863 Å2 / Biso min: 48.87 Å2
Refinement stepCycle: final / Resolution: 2.49→68.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4089 0 60 22 4171
Biso mean--68.93 67.21 -
Num. residues----542
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2415X-RAY DIFFRACTION9.62TORSIONAL
12B2415X-RAY DIFFRACTION9.62TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.49-2.590.47331470.4742725287298
2.59-2.710.36261570.33092801295899
2.71-2.850.34831580.27442769292799
2.85-3.030.31441510.28592819297099
3.03-3.260.33251660.2972714288098
3.26-3.590.25651250.22282836296199
3.59-4.110.2691240.20352797292199
4.11-5.180.17551550.17432799295499
5.18-68.040.19481470.18232827297498
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)
12.25490.8069-0.25091.0708-1.265.7349-0.48110.3187-0.2704-0.8575-0.5682-0.49171.26320.3454-0.03311.3420.21450.49830.71830.04551.218379.58979.9933-3.2845
21.42251.2189-2.0531.6374-1.31581.5185-0.3318-0.2396-0.2261-0.2892-0.04160.00210.3431-0.0823-0.04230.87510.04640.11410.7511-0.01160.852675.705619.01910.4722
31.55440.4239-0.44884.8436-0.59752.2950.1569-0.4407-0.26780.1927-0.2455-0.53270.12550.14130.0020.63810.0356-0.05460.71760.04980.685969.274915.246915.1153
41.0411-0.73760.89050.7899-1.07151.01510.22580.02260.1095-0.1295-0.08690.073-0.2334-0.3846-00.81960.03170.04670.818-0.0250.68159.636426.217413.6976
50.2925-0.1968-0.07840.6734-0.53370.84870.1716-0.0152-0.6717-0.109-0.1391.92870.6348-1.3025-0.07230.9170.0070.17431.06190.12431.138246.401920.908219.1294
60.75890.48660.28750.9402-0.36950.50410.1485-0.5487-0.02861.6588-0.13440.3215-0.8852-0.1381-0.00031.26560.00890.08161.1427-0.05360.766358.766225.730829.0506
73.0604-0.12681.78264.68332.59435.4811-0.26770.00230.5895-0.3375-0.45920.9114-0.1107-0.3303-0.09180.47040.0349-0.13140.54020.0091.053648.1281-11.82193.6806
81.2147-0.22930.42932.36530.80970.9093-0.05-0.19370.11310.4275-0.14570.4470.04960.0548-0.00020.85240.03380.05410.69750.02530.654861.3894-14.105919.8622
90.3418-0.6333-0.44691.947-0.39430.8167-0.0713-0.00260.04580.0303-0.0367-0.620.0630.2127-00.85710.0521-0.01940.78860.03820.734875.2062-19.695620.3384
100.82140.03920.97780.43920.06511.26040.13-0.1027-0.05791.1091-0.21440.03230.5521-0.033701.07650.03550.05920.79790.05890.602168.1406-22.182632.0233
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'B' and (resid 76 through 129 )B76 - 129
2X-RAY DIFFRACTION2chain 'B' and (resid 130 through 164 )B130 - 164
3X-RAY DIFFRACTION3chain 'B' and (resid 165 through 249 )B165 - 249
4X-RAY DIFFRACTION4chain 'B' and (resid 250 through 301 )B250 - 301
5X-RAY DIFFRACTION5chain 'B' and (resid 302 through 329 )B302 - 329
6X-RAY DIFFRACTION6chain 'B' and (resid 330 through 361 )B330 - 361
7X-RAY DIFFRACTION7chain 'A' and (resid 78 through 188 )A78 - 188
8X-RAY DIFFRACTION8chain 'A' and (resid 189 through 270 )A189 - 270
9X-RAY DIFFRACTION9chain 'A' and (resid 271 through 329 )A271 - 329
10X-RAY DIFFRACTION10chain 'A' and (resid 330 through 361 )A330 - 361

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