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- PDB-9ckn: Histidine-covalent alpha-helical peptide (compound 6) targeting hMcl-1 -

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Basic information

Entry
Database: PDB / ID: 9ckn
TitleHistidine-covalent alpha-helical peptide (compound 6) targeting hMcl-1
Components
  • Helical Peptide
  • Induced myeloid leukemia cell differentiation protein Mcl-1
KeywordsAPOPTOSIS / Histidine-covalent stapled alpha-helical peptides
Function / homology
Function and homology information


positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cell fate determination / cellular homeostasis / mitochondrial fusion / Bcl-2 family protein complex / BH domain binding / 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 / cell fate determination / cellular homeostasis / mitochondrial fusion / Bcl-2 family protein complex / BH domain binding / 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 / intrinsic apoptotic signaling pathway in response to DNA damage / Signaling by ALK fusions and activated point mutants / channel activity / Interleukin-4 and Interleukin-13 signaling / regulation of apoptotic process / mitochondrial outer membrane / positive regulation of apoptotic process / protein heterodimerization activity / DNA damage response / negative regulation of apoptotic process / 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-2 family / BCL (B-Cell lymphoma); contains BH1, BH2 regions / Bcl2-like ...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-2 family / BCL (B-Cell lymphoma); contains BH1, BH2 regions / Bcl2-like / Bcl-2, Bcl-2 homology region 1-3 / Apoptosis regulator proteins, Bcl-2 family / BCL2-like apoptosis inhibitors family profile. / Bcl-2-like superfamily
Similarity search - Domain/homology
Induced myeloid leukemia cell differentiation protein Mcl-1
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsMuzzarelli, K.M. / Assar, Z. / Alboreggia, G. / Pellecchia, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Covalent Targeting of Histidine Residues with Aryl Fluorosulfates: Application to Mcl-1 BH3 Mimetics.
Authors: Alboreggia, G. / Udompholkul, P. / Atienza, E.L. / Muzzarelli, K. / Assar, Z. / Pellecchia, M.
History
DepositionJul 9, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2024Provider: repository / Type: Initial release

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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
D: Helical Peptide
E: Helical Peptide


Theoretical massNumber of molelcules
Total (without water)38,8944
Polymers38,8944
Non-polymers00
Water1,856103
1
A: Induced myeloid leukemia cell differentiation protein Mcl-1
E: Helical Peptide


Theoretical massNumber of molelcules
Total (without water)19,4472
Polymers19,4472
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1680 Å2
ΔGint-10 kcal/mol
Surface area8200 Å2
MethodPISA
2
B: Induced myeloid leukemia cell differentiation protein Mcl-1
D: Helical Peptide


Theoretical massNumber of molelcules
Total (without water)19,4472
Polymers19,4472
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1700 Å2
ΔGint-12 kcal/mol
Surface area7870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)31.064, 77.636, 61.755
Angle α, β, γ (deg.)90.000, 91.690, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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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: 17850.330 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: Protein/peptide Helical Peptide


Mass: 1596.812 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 103 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.08 Å3/Da / Density % sol: 35.68 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: 0.1 M Citric acid, pH 3.5, and 25% (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9537 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 28, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.5→48.32 Å / Num. obs: 45530 / % possible obs: 96.54 % / Redundancy: 9 % / Biso Wilson estimate: 27.56 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.05617 / Net I/σ(I): 15.4
Reflection shellResolution: 1.501→1.554 Å / Num. unique obs: 4321 / CC1/2: 0.325

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→48.32 Å / SU ML: 0.2989 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 31.1154
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2427 2059 4.55 %
Rwork0.2192 43148 -
obs0.2203 45207 96.54 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 39.85 Å2
Refinement stepCycle: LAST / Resolution: 1.5→48.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2321 0 222 103 2646
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00972580
X-RAY DIFFRACTIONf_angle_d1.44053462
X-RAY DIFFRACTIONf_chiral_restr0.0745382
X-RAY DIFFRACTIONf_plane_restr0.0179443
X-RAY DIFFRACTIONf_dihedral_angle_d15.26611016
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.540.40821240.39812690X-RAY DIFFRACTION90.28
1.54-1.570.35851190.37092816X-RAY DIFFRACTION94.19
1.57-1.620.34961440.38732722X-RAY DIFFRACTION91.92
1.62-1.660.40731570.35912842X-RAY DIFFRACTION97.06
1.66-1.720.3171360.30272902X-RAY DIFFRACTION97.34
1.72-1.780.30571480.27342894X-RAY DIFFRACTION97.88
1.78-1.850.26631280.26512927X-RAY DIFFRACTION98.07
1.85-1.930.29221340.26272914X-RAY DIFFRACTION97.85
1.93-2.040.29521270.25072917X-RAY DIFFRACTION98.32
2.04-2.160.30681420.22492866X-RAY DIFFRACTION96.6
2.16-2.330.27941220.212780X-RAY DIFFRACTION93.07
2.33-2.570.23251490.20672955X-RAY DIFFRACTION99.04
2.57-2.940.21261260.20942971X-RAY DIFFRACTION99.33
2.94-3.70.22791560.20362978X-RAY DIFFRACTION99.65
3.7-48.320.20791470.19062974X-RAY DIFFRACTION97.68
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)
11.48605348734-0.7830965309030.2889572384051.36422036248-1.938442638873.491768334730.006650911910710.01691245584890.043449079988-0.0150633042872-0.0212898768386-0.1085815251770.0277027969335-0.06737451828572.10743632154E-90.116414351315-0.002577322901060.007609408925020.09539956570620.00316881794360.14002210918313.253663151910.2970237481.63994157184
21.85497630364-0.06876544042350.1243856629482.16712371849-1.428698792324.58513877674-0.094355781495-0.09842648488820.015948124698-0.1934941279780.03677003657270.161843007457-0.0637989697532-0.09409743206444.23159700923E-90.1684203587150.00659588335737-0.02286012959760.1359324533920.01476126158530.169615652016-2.2286182871427.031873072329.5537991675
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Label seq-ID: 1

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-ID
11(chain A and resseq 169:401)AA - B169 - 401
22(chain B and resseq 172:401)BC - D172 - 401

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