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- PDB-6fs2: MCL1 in complex with indole acid ligand -

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Basic information

Entry
Database: PDB / ID: 6fs2
TitleMCL1 in complex with indole acid ligand
ComponentsInduced myeloid leukemia cell differentiation protein Mcl-1
KeywordsIMMUNE SYSTEM / MCL1 / indole acid
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 / Blc2-like / Apoptosis Regulator Bcl-x / 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 ...Apoptosis regulator, Mcl-1 / Blc2-like / Apoptosis Regulator Bcl-x / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-E4K / Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 2.55 Å
AuthorsHargreaves, D.
CitationJournal: Nat Commun / Year: 2018
Title: Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia.
Authors: Tron, A.E. / Belmonte, M.A. / Adam, A. / Aquila, B.M. / Boise, L.H. / Chiarparin, E. / Cidado, J. / Embrey, K.J. / Gangl, E. / Gibbons, F.D. / Gregory, G.P. / Hargreaves, D. / Hendricks, J.A. ...Authors: Tron, A.E. / Belmonte, M.A. / Adam, A. / Aquila, B.M. / Boise, L.H. / Chiarparin, E. / Cidado, J. / Embrey, K.J. / Gangl, E. / Gibbons, F.D. / Gregory, G.P. / Hargreaves, D. / Hendricks, J.A. / Johannes, J.W. / Johnstone, R.W. / Kazmirski, S.L. / Kettle, J.G. / Lamb, M.L. / Matulis, S.M. / Nooka, A.K. / Packer, M.J. / Peng, B. / Rawlins, P.B. / Robbins, D.W. / Schuller, A.G. / Su, N. / Yang, W. / Ye, Q. / Zheng, X. / Secrist, J.P. / Clark, E.A. / Wilson, D.M. / Fawell, S.E. / Hird, A.W.
History
DepositionFeb 18, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 26, 2018Provider: repository / Type: Initial release
Revision 2.0Oct 2, 2019Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Other / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / cell ...atom_site / cell / entity / entity_name_com / entity_poly / entity_poly_seq / entity_src_gen / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_unobs_or_zero_occ_residues / struct_asym / struct_ref / struct_ref_seq
Item: _atom_site.label_entity_id / _cell.Z_PDB ..._atom_site.label_entity_id / _cell.Z_PDB / _pdbx_entity_nonpoly.entity_id / _pdbx_nonpoly_scheme.entity_id / _struct_asym.entity_id / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.ref_id / _struct_ref_seq.seq_align_end
Revision 2.1May 8, 2024Group: Advisory / Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)36,9326
Polymers35,1742
Non-polymers1,7584
Water72140
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A: Induced myeloid leukemia cell differentiation protein Mcl-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,4663
Polymers17,5871
Non-polymers8792
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)18,4663
Polymers17,5871
Non-polymers8792
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)46.710, 46.710, 47.493
Angle α, β, γ (deg.)74.74, 74.74, 61.83
Int Tables number1
Space group name H-MP1

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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: 17586.943 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-E4K / 7-(2-methylphenyl)-3-[3-(5,6,7,8-tetrahydronaphthalen-1-yloxy)propyl]-1~{H}-indole-2-carboxylic acid


Mass: 439.545 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C29H29NO3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 40 / 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: 2.51 Å3/Da / Density % sol: 51.07 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: unknown

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Feb 9, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.55→45.22 Å / Num. obs: 10721 / % possible obs: 97.2 % / Redundancy: 2 % / Biso Wilson estimate: 53.55 Å2 / Net I/σ(I): 8.55
Reflection shellResolution: 2.55→2.75 Å / Redundancy: 2 % / Mean I/σ(I) obs: 2.05 / % possible all: 96.1

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Processing

Software
NameVersionClassification
iMOSFLMdata reduction
SCALAdata scaling
BUSTER2.11.6refinement
PHASERphasing
RefinementResolution: 2.55→45.2 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.873 / Rfactor Rfree error: 0.03 / SU R Cruickshank DPI: 0.7 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.81 / SU Rfree Blow DPI: 0.307 / SU Rfree Cruickshank DPI: 0.322
RfactorNum. reflection% reflectionSelection details
Rfree0.254 947 8.83 %RANDOM
Rwork0.186 ---
obs0.192 10720 97.5 %-
Displacement parametersBiso mean: 40.9 Å2
Baniso -1Baniso -2Baniso -3
1-2.4214 Å23.0055 Å22.0775 Å2
2--1.7989 Å22.1198 Å2
3----4.2204 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: LAST / Resolution: 2.55→45.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2336 0 132 40 2508
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012626HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.053541HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d957SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes67HARMONIC2
X-RAY DIFFRACTIONt_gen_planes373HARMONIC5
X-RAY DIFFRACTIONt_it2626HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.69
X-RAY DIFFRACTIONt_other_torsion20.09
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion314SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3117SEMIHARMONIC4
LS refinement shellResolution: 2.55→2.85 Å / Rfactor Rfree error: 0 / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.273 267 8.77 %
Rwork0.226 2777 -
all0.231 3044 -
obs--96.88 %

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