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- PDB-6o5z: Crystal Structure of the human MLKL pseudokinase domain bound to ... -

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Basic information

Entry
Database: PDB / ID: 6o5z
TitleCrystal Structure of the human MLKL pseudokinase domain bound to compound 2
ComponentsMixed lineage kinase domain-like protein
Keywordstransferase/transferase inhibitor / Pseudokinase / Inhibitor / Necroptosis / TRANSFERASE / transferase-transferase inhibitor complex
Function / homology
Function and homology information


execution phase of necroptosis / Microbial modulation of RIPK1-mediated regulated necrosis / necroptotic signaling pathway / RIPK1-mediated regulated necrosis / TRP channels / protein homotrimerization / necroptotic process / Regulation of necroptotic cell death / cell junction / defense response to virus ...execution phase of necroptosis / Microbial modulation of RIPK1-mediated regulated necrosis / necroptotic signaling pathway / RIPK1-mediated regulated necrosis / TRP channels / protein homotrimerization / necroptotic process / Regulation of necroptotic cell death / cell junction / defense response to virus / cell surface receptor signaling pathway / protein-containing complex binding / protein kinase binding / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / Mixed lineage kinase domain-like N-terminal domain / Adaptor protein Cbl, N-terminal domain superfamily / : / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-LN4 / Mixed lineage kinase domain-like protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.285 Å
AuthorsCowan, A.D. / Murphy, J.M. / Pierotti, C.L. / Lessene, G.L. / Czabotar, P.E.
Funding support Australia, 3items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)1105754 Australia
National Health and Medical Research Council (NHMRC, Australia)1124735 Australia
National Health and Medical Research Council (NHMRC, Australia)9000433 Australia
CitationJournal: Acs Chem.Biol. / Year: 2020
Title: Potent Inhibition of Necroptosis by Simultaneously Targeting Multiple Effectors of the Pathway.
Authors: Pierotti, C.L. / Tanzer, M.C. / Jacobsen, A.V. / Hildebrand, J.M. / Garnier, J.M. / Sharma, P. / Lucet, I.S. / Cowan, A.D. / Kersten, W.J.A. / Luo, M.X. / Liang, L.Y. / Fitzgibbon, C. / ...Authors: Pierotti, C.L. / Tanzer, M.C. / Jacobsen, A.V. / Hildebrand, J.M. / Garnier, J.M. / Sharma, P. / Lucet, I.S. / Cowan, A.D. / Kersten, W.J.A. / Luo, M.X. / Liang, L.Y. / Fitzgibbon, C. / Garnish, S.E. / Hempel, A. / Nachbur, U. / Huang, D.C.S. / Czabotar, P.E. / Silke, J. / van Delft, M.F. / Murphy, J.M. / Lessene, G.
History
DepositionMar 4, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 16, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 3, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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: Mixed lineage kinase domain-like protein
B: Mixed lineage kinase domain-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,3598
Polymers65,4742
Non-polymers8866
Water1,856103
1
A: Mixed lineage kinase domain-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9855
Polymers32,7371
Non-polymers2484
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Mixed lineage kinase domain-like protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3743
Polymers32,7371
Non-polymers6382
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)50.161, 118.845, 52.761
Angle α, β, γ (deg.)90.000, 116.780, 90.000
Int Tables number4
Space group name H-MP1211
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 191 through 234 or resid 241...
21(chain B and (resid 191 through 350 or resid 365 or resid 368 through 467))

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
11GLUGLULYSLYS(chain A and (resid 191 through 234 or resid 241...AA191 - 2347 - 50
12ALAALAPHEPHE(chain A and (resid 191 through 234 or resid 241...AA241 - 35057 - 166
13ARGARGARGARG(chain A and (resid 191 through 234 or resid 241...AA353169
14THRTHRTHRTHR(chain A and (resid 191 through 234 or resid 241...AA357173
15ASPASPSERSER(chain A and (resid 191 through 234 or resid 241...AA369 - 467185 - 283
21GLUGLUPHEPHE(chain B and (resid 191 through 350 or resid 365 or resid 368 through 467))BB191 - 3507 - 166
22ARGARGARGARG(chain B and (resid 191 through 350 or resid 365 or resid 368 through 467))BB365181
23THRTHRSERSER(chain B and (resid 191 through 350 or resid 365 or resid 368 through 467))BB368 - 467184 - 283

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Components

#1: Protein Mixed lineage kinase domain-like protein / hMLKL


Mass: 32736.750 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MLKL / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8NB16
#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-LN4 / 1-[2-fluoranyl-5-(trifluoromethyl)phenyl]-3-[4-[methyl-[2-[(3-sulfamoylphenyl)amino]pyrimidin-4-yl]amino]phenyl]urea


Mass: 575.538 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H21F4N7O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 103 / Source method: isolated from a natural source / Formula: H2O

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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: 2.3 Å3/Da / Density % sol: 46.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.88
Details: 0.18 M magnesium chloride, 26.8% (w/v) PEG 3350, 0.1 M sodium HEPES pH 7.88

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 30, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 2.28→47.08 Å / Num. obs: 24748 / % possible obs: 98.9 % / Redundancy: 3.8 % / CC1/2: 0.997 / Rmerge(I) obs: 0.114 / Rpim(I) all: 0.068 / Rrim(I) all: 0.133 / Net I/σ(I): 10.2 / Num. measured all: 93506
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.28-2.363.71.408808322050.4130.8471.6461.190
8.85-47.083.60.0216294490.9990.0120.02344.599.5

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Processing

Software
NameClassification
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4MWI

4mwi


Resolution: 2.285→47.103 Å / SU ML: 0.34 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 26.93 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2321 2446 9.91 %
Rwork0.1829 22241 -
obs0.1878 24687 98.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 162.82 Å2 / Biso mean: 61.4541 Å2 / Biso min: 21.93 Å2
Refinement stepCycle: final / Resolution: 2.285→47.103 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4289 0 90 103 4482
Biso mean--74.94 50.38 -
Num. residues----531
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2492X-RAY DIFFRACTION9.454TORSIONAL
12B2492X-RAY DIFFRACTION9.454TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 17

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.2853-2.33190.3781220.33841069119183
2.3319-2.38260.38351470.32813241471100
2.3826-2.4380.35461600.281912871447100
2.438-2.4990.28871260.271913461472100
2.499-2.56660.30231280.255813281456100
2.5666-2.64210.33061660.24813171483100
2.6421-2.72740.27321360.235413101446100
2.7274-2.82480.30421470.224213211468100
2.8248-2.93790.30481560.207113111467100
2.9379-3.07160.25091350.196713101445100
3.0716-3.23350.24461610.194413181479100
3.2335-3.4360.21931360.16613191455100
3.436-3.70120.20721390.164413381477100
3.7012-4.07350.21281510.144613361487100
4.0735-4.66250.17281310.139513351466100
4.6625-5.87250.1891440.158213331477100
5.8725-47.11330.19141610.154413391500100
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)
15.8966-0.4490.13218.1635-1.6778.4540.04690.37110.0395-0.54950.35780.9731-0.409-0.4103-0.37610.30850.0048-0.11120.48430.05920.5003-34.35359.877746.4758
23.07660.58330.24834.68120.2972.87330.03590.18630.0215-0.1938-0.02440.3887-0.0201-0.33440.01590.32020.0625-0.0460.37010.02390.3661-22.29414.842653.2306
32.1129-2.58920.50853.2157-0.57810.15260.27770.56360.5324-1.0974-0.22530.6255-0.0989-0.3838-0.03320.65150.0736-0.10990.73580.09790.6042-24.173226.685548.8843
42.87370.7568-1.31724.63980.17473.2135-0.0811-0.13670.1880.273-0.01240.1231-0.90290.04880.05360.62930.053-0.10980.3224-0.05330.3511-12.729832.066261.0697
56.2211-0.8291-0.13916.9093-1.20547.7959-0.161-0.0147-0.40240.1858-0.185-1.05680.24750.41320.24770.29070.0148-0.10460.46220.10230.7717-6.0967-2.528156.8553
62.61331.1818-0.25434.0939-1.33162.56150.04950.1638-0.20770.2479-0.0542-0.58290.14070.1378-0.04120.30330.0424-0.09140.2788-0.00540.3879-18.7588-6.346559.224
75.1255-0.85622.22674.2272-2.85154.9958-0.56310.4518-0.1577-0.28860.33120.1121-0.26040.66030.13510.519-0.04770.03460.4911-0.0320.3057-22.278-23.88866.1245
84.95410.09940.70313.9084-0.58814.28370.006-0.0932-0.03290.8150.19610.9034-0.134-0.525-0.17970.4303-0.02480.14590.37550.05440.418-35.7308-18.107670.3395
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 191 through 240 )A191 - 240
2X-RAY DIFFRACTION2chain 'A' and (resid 241 through 344 )A241 - 344
3X-RAY DIFFRACTION3chain 'A' and (resid 345 through 371 )A345 - 371
4X-RAY DIFFRACTION4chain 'A' and (resid 372 through 470 )A372 - 470
5X-RAY DIFFRACTION5chain 'B' and (resid 190 through 222 )B190 - 222
6X-RAY DIFFRACTION6chain 'B' and (resid 223 through 347 )B223 - 347
7X-RAY DIFFRACTION7chain 'B' and (resid 348 through 390 )B348 - 390
8X-RAY DIFFRACTION8chain 'B' and (resid 391 through 467 )B391 - 467

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