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- PDB-8h7b: The crystal structure of human mcl1 kinase domain in complex with... -

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Basic information

Entry
Database: PDB / ID: 8h7b
TitleThe crystal structure of human mcl1 kinase domain in complex with MCL1-M-EBA
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
KeywordsTRANSFERASE / Complex / inhibitor / lysine
Function / homology
Function and homology information


positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cellular homeostasis / cell fate determination / mitochondrial fusion / channel activity / Bcl-2 family protein complex / BH3 domain binding / negative regulation of anoikis / protein transmembrane transporter activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cellular homeostasis / cell fate determination / mitochondrial fusion / channel activity / Bcl-2 family protein complex / BH3 domain binding / negative regulation of anoikis / protein transmembrane transporter activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of autophagy / release of cytochrome c from mitochondria / response to cytokine / Signaling by ALK fusions and activated point mutants / intrinsic apoptotic signaling pathway in response to DNA damage / regulation of apoptotic process / Interleukin-4 and Interleukin-13 signaling / mitochondrial outer membrane / positive regulation of apoptotic process / protein heterodimerization activity / DNA damage response / negative regulation of apoptotic process / protein homodimerization activity / mitochondrion / nucleoplasm / membrane / nucleus / cytosol / cytoplasm
Similarity search - Function
Apoptosis regulator, Mcl-1 / Apoptosis regulator, Bcl-2, BH3 motif, conserved site / Apoptosis regulator, Bcl-2 family BH3 motif signature. / Apoptosis regulator, Bcl-2, BH1 motif, conserved site / Apoptosis regulator, Bcl-2 family BH1 motif signature. / Apoptosis regulator, Bcl-2, BH2 motif, conserved site / Apoptosis regulator, Bcl-2 family BH2 motif signature. / BCL (B-Cell lymphoma); contains BH1, BH2 regions / Bcl-2 family / Bcl-2, Bcl-2 homology region 1-3 ...Apoptosis regulator, Mcl-1 / Apoptosis regulator, Bcl-2, BH3 motif, conserved site / Apoptosis regulator, Bcl-2 family BH3 motif signature. / Apoptosis regulator, Bcl-2, BH1 motif, conserved site / Apoptosis regulator, Bcl-2 family BH1 motif signature. / Apoptosis regulator, Bcl-2, BH2 motif, conserved site / Apoptosis regulator, Bcl-2 family BH2 motif signature. / BCL (B-Cell lymphoma); contains BH1, BH2 regions / Bcl-2 family / Bcl-2, Bcl-2 homology region 1-3 / Bcl2-like / Apoptosis regulator proteins, Bcl-2 family / BCL2-like apoptosis inhibitors family profile. / Bcl-2-like superfamily
Similarity search - Domain/homology
Chem-QHR / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4640844632 Å
AuthorsZhu, C.J. / Zhang, Z.M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Am.Chem.Soc. / Year: 2023
Title: 2-Ethynylbenzaldehyde-Based, Lysine-Targeting Irreversible Covalent Inhibitors for Protein Kinases and Nonkinases.
Authors: Chen, P. / Tang, G. / Zhu, C. / Sun, J. / Wang, X. / Xiang, M. / Huang, H. / Wang, W. / Li, L. / Zhang, Z.M. / Gao, L. / Yao, S.Q.
History
DepositionOct 19, 2022Deposition site: PDBJ / Processing site: PDBE
Revision 1.0Feb 22, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Data collection / Derived calculations ...Data collection / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / entity / pdbx_entity_nonpoly / struct_ncs_dom_lim
Item: _chem_comp.name / _entity.pdbx_description ..._chem_comp.name / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _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
Revision 1.2Feb 7, 2024Group: Refinement description / Category: pdbx_initial_refinement_model / Item: _pdbx_initial_refinement_model.accession_code

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Induced myeloid leukemia cell differentiation protein Mcl-1
B: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0114
Polymers34,8182
Non-polymers1,1932
Water5,008278
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,0062
Polymers17,4091
Non-polymers5971
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,0062
Polymers17,4091
Non-polymers5971
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)58.248, 63.205, 83.548
Angle α, β, γ (deg.)90.0, 90.0, 90.0
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21

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
11SERSERASPASPchain 'A'AA171 - 1951 - 25
12GLYGLYVALVALchain 'A'AA203 - 32133 - 151
23SERSERASPASPchain 'B'BB171 - 1951 - 25
24GLYGLYVALVALchain 'B'BB203 - 32133 - 151

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Components

#1: Protein Induced myeloid leukemia cell differentiation protein Mcl-1 / Bcl-2-like protein 3 / Bcl2-L-3 / Bcl-2-related protein EAT/mcl1 / mcl1/EAT


Mass: 17408.844 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MCL1, BCL2L3 / Production host: Escherichia coli (E. coli) / References: UniProt: Q07820
#2: Chemical ChemComp-QHR / 7-[3-(isoquinolin-7-yloxymethyl)-1,5-dimethyl-pyrazol-4-yl]-3-(3-naphthalen-1-yloxypropyl)-1H-indole-2-carboxylic acid


Mass: 596.674 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C37H32N4O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 278 / 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: 2.07 Å3/Da / Density % sol: 40.69 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 18% (v/v) 2-Propanol, 0.1 M sodium citrate, pH 5.5 and 20% (w/v) PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.97 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Sep 4, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 1.464→50.41 Å / Num. obs: 44015 / % possible obs: 99.8 % / Redundancy: 7.8 % / CC1/2: 0.996 / Net I/σ(I): 11.2
Reflection shellResolution: 1.464→1.514 Å / Num. unique obs: 44015 / CC1/2: 0.749

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Processing

Software
NameVersionClassification
PHENIX1.9_1692+SVNrefinement
HKL-3000data reduction
XDSdata scaling
PHENIXphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7W7Y

7w7y


Resolution: 1.4640844632→50.4060252674 Å / SU ML: 0.160869911775 / Cross valid method: FREE R-VALUE / σ(F): 1.34357632039 / Phase error: 24.5440080615
RfactorNum. reflection% reflection
Rfree0.197426713823 2168 4.92660091806 %
Rwork0.16786074695 41838 -
obs0.169429766062 44006 81.7803382271 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.8511827776 Å2
Refinement stepCycle: LAST / Resolution: 1.4640844632→50.4060252674 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2391 0 0 278 2669
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.006502731995452442
X-RAY DIFFRACTIONf_angle_d0.9407195205433309
X-RAY DIFFRACTIONf_chiral_restr0.0344564220585362
X-RAY DIFFRACTIONf_plane_restr0.00449156432468412
X-RAY DIFFRACTIONf_dihedral_angle_d17.852131347881
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4641-1.49810.285180958013180.212019400069399X-RAY DIFFRACTION11.7896522477
1.4981-1.53560.272704839181480.2190511315611164X-RAY DIFFRACTION34.2566421707
1.5356-1.57710.3107899541081320.2142010747792359X-RAY DIFFRACTION70.2679830748
1.5771-1.62350.2630159507551690.205153367633206X-RAY DIFFRACTION95.5549263873
1.6235-1.6760.2484084317421750.1859924522073303X-RAY DIFFRACTION98.554831397
1.676-1.73590.2464338401481300.1813644009252771X-RAY DIFFRACTION81.5804274466
1.7359-1.80540.227288452661350.1773704278833431X-RAY DIFFRACTION100
1.8054-1.88750.2609175972861240.1907544111882759X-RAY DIFFRACTION98.5978112175
1.8875-1.9870.195459099831180.1855328603022358X-RAY DIFFRACTION74.3990384615
1.987-2.11150.2072167176361800.1643696019313401X-RAY DIFFRACTION99.9720826354
2.1115-2.27460.2122162944511900.1652171152443396X-RAY DIFFRACTION100
2.2746-2.50350.225241473151660.1646448022773437X-RAY DIFFRACTION100
2.5035-2.86570.2049629067991930.17106854353066X-RAY DIFFRACTION89.7796143251
2.8657-3.61030.1729754955811860.1647292726073326X-RAY DIFFRACTION95.8776958777
3.6103-50.40.1705461097522040.1560250890513462X-RAY DIFFRACTION96.0188580409

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