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- PDB-7nb7: Structure of Mcl-1 complex with compound 6b -

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Basic information

Entry
Database: PDB / ID: 7nb7
TitleStructure of Mcl-1 complex with compound 6b
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS / APOPTOSIS-INHIBITOR COMPLEX / MCL-1 / S64315 / SMALL MOLECULE INHIBITOR / SBDD
Function / homology
Function and homology information


positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cellular homeostasis / cell fate determination / channel activity / mitochondrial fusion / Bcl-2 family protein complex / BH3 domain binding / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / protein transmembrane transporter activity ...positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cellular homeostasis / cell fate determination / channel activity / mitochondrial fusion / Bcl-2 family protein complex / BH3 domain binding / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / protein transmembrane transporter activity / extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of autophagy / release of cytochrome c from mitochondria / response to cytokine / intrinsic apoptotic signaling pathway in response to DNA damage / Signaling by ALK fusions and activated point mutants / 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 / cytoplasm / cytosol
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-U6N / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.82 Å
AuthorsDokurno, P. / Surgenor, A.E. / Kotschy, A.
CitationJournal: Acs Omega / Year: 2021
Title: The Effect of Core Replacement on S64315, a Selective MCL-1 Inhibitor, and Its Analogues.
Authors: Sipos, S. / Balint, B. / Szabo, Z.B. / Ondi, L. / Csekei, M. / Szlavik, Z. / Proszenyak, A. / Murray, J.B. / Davidson, J. / Chen, I. / Dokurno, P. / Surgenor, A.E. / Pedder, C. / Hubbard, R. ...Authors: Sipos, S. / Balint, B. / Szabo, Z.B. / Ondi, L. / Csekei, M. / Szlavik, Z. / Proszenyak, A. / Murray, J.B. / Davidson, J. / Chen, I. / Dokurno, P. / Surgenor, A.E. / Pedder, C. / Hubbard, R.E. / Maragno, A.L. / Chanrion, M. / Colland, F. / Geneste, O. / Kotschy, A.
History
DepositionJan 25, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 13, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / diffrn_source / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _diffrn_source.pdbx_synchrotron_site / _struct_ncs_dom_lim.beg_auth_comp_id ..._diffrn_source.pdbx_synchrotron_site / _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: Induced myeloid leukemia cell differentiation protein Mcl-1
B: Induced myeloid leukemia cell differentiation protein Mcl-1
C: Induced myeloid leukemia cell differentiation protein Mcl-1
D: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)79,9218
Polymers77,9734
Non-polymers1,9484
Water1086
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,9802
Polymers19,4931
Non-polymers4871
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)19,9802
Polymers19,4931
Non-polymers4871
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,9802
Polymers19,4931
Non-polymers4871
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,9802
Polymers19,4931
Non-polymers4871
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)89.281, 166.106, 44.874
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: SER / Beg label comp-ID: SER / End auth comp-ID: HIS / End label comp-ID: HIS / Refine code: _ / Auth seq-ID: 170 - 320 / Label seq-ID: 13 - 163

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12AA
22CC
13AA
23DD
14BB
24CC
15BB
25DD
16CC
26DD

NCS ensembles :
ID
1
2
3
4
5
6

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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: 19493.154 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MCL1, BCL2L3 / Production host: Escherichia coli BL21 (bacteria) / Variant (production host): pLysS / References: UniProt: Q07820
#2: Chemical
ChemComp-U6N / (2~{R})-2-[[7-but-2-ynyl-5-(3-chloranyl-2-methyl-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid


Mass: 486.993 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C28H27ClN4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / 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: 2.13 Å3/Da / Density % sol: 42.35 %
Crystal growTemperature: 284 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 1.8 M Ammonium citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9763 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 24, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.82→28.8 Å / Num. obs: 16409 / % possible obs: 98.3 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.28 / Net I/σ(I): 4.7
Reflection shellResolution: 2.82→2.89 Å / Redundancy: 3.3 % / Rmerge(I) obs: 1.1 / Mean I/σ(I) obs: 0.9 / Num. unique obs: 0 / % possible all: 95.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMAC5.8.0258refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6qz6

6qz6


Resolution: 2.82→20 Å / Cor.coef. Fo:Fc: 0.876 / Cor.coef. Fo:Fc free: 0.81 / SU B: 28.202 / SU ML: 0.486 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.473 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2912 802 4.9 %RANDOM
Rwork0.2523 ---
obs0.2542 15525 97.15 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 170.47 Å2 / Biso mean: 37.281 Å2 / Biso min: 12.18 Å2
Baniso -1Baniso -2Baniso -3
1-0.5 Å20 Å20 Å2
2---1.32 Å20 Å2
3---0.82 Å2
Refinement stepCycle: final / Resolution: 2.82→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4745 0 140 6 4891
Biso mean--22.74 42.62 -
Num. residues----604
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0134973
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174635
X-RAY DIFFRACTIONr_angle_refined_deg1.4481.6416711
X-RAY DIFFRACTIONr_angle_other_deg1.281.58410642
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8435600
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.54420.691275
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.35915864
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.2231549
X-RAY DIFFRACTIONr_chiral_restr0.0650.2640
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.025566
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021145
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A49150.12
12B49150.12
21A48360.11
22C48360.11
31A48520.12
32D48520.12
41B48760.11
42C48760.11
51B49390.1
52D49390.1
61C48800.11
62D48800.11
LS refinement shellResolution: 2.82→2.969 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.336 102 -
Rwork0.36 2223 -
all-2325 -
obs--98.94 %

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