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- PDB-9tlw: De novo designed single-chain antiparallel coiled-coil hairpin wi... -

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Basic information

Entry
Database: PDB / ID: 9tlw
TitleDe novo designed single-chain antiparallel coiled-coil hairpin with binding site for MCL-1, Sc-apCC-2-MCL-1-4 in complex with MCL-1
Components
  • Induced myeloid leukemia cell differentiation protein Mcl-1
  • Sc-apCC-2-MCL-1-4
KeywordsDE NOVO PROTEIN / Protein Binder / Computational Design / Coiled-coil / complex
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 / negative regulation of anoikis / extrinsic apoptotic signaling pathway in absence of ligand / BH3 domain binding / transmembrane protein 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 / negative regulation of anoikis / extrinsic apoptotic signaling pathway in absence of ligand / BH3 domain binding / transmembrane protein transporter activity / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / release of cytochrome c from mitochondria / response to cytokine / negative regulation of autophagy / intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of neuron apoptotic process / 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 / negative regulation of apoptotic process / DNA damage response / 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 speciessynthetic construct (others)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsMylemans, B. / Acevedo-Jake, A. / Wilson, A.J. / Woolfson, D.N.
Funding support United Kingdom, 4items
OrganizationGrant numberCountry
Biotechnology and Biological Sciences Research Council (BBSRC)BB/V006231/1 United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/V006703/1 United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/V008412/1 United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/V008412/2 United Kingdom
CitationJournal: J.Am.Chem.Soc. / Year: 2026
Title: De Novo-Designed Bifunctional
Authors: Mylemans, B. / Korona, B. / Acevedo-Jake, A.M. / MacRae, A. / Edwards, T.A. / Huang, D.T. / Wilson, A.J. / Itzhaki, L.S. / Woolfson, D.N.
History
DepositionDec 11, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 19, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Sc-apCC-2-MCL-1-4
B: Induced myeloid leukemia cell differentiation protein Mcl-1
C: Sc-apCC-2-MCL-1-4
D: Induced myeloid leukemia cell differentiation protein Mcl-1


Theoretical massNumber of molelcules
Total (without water)52,6464
Polymers52,6464
Non-polymers00
Water724
1
A: Sc-apCC-2-MCL-1-4
B: Induced myeloid leukemia cell differentiation protein Mcl-1


Theoretical massNumber of molelcules
Total (without water)26,3232
Polymers26,3232
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Sc-apCC-2-MCL-1-4
D: Induced myeloid leukemia cell differentiation protein Mcl-1


Theoretical massNumber of molelcules
Total (without water)26,3232
Polymers26,3232
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)50.353, 83.881, 63.379
Angle α, β, γ (deg.)90.000, 113.005, 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
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
d_1ens_1(chain "C" and (resid 2 through 22 or (resid 23...
d_2ens_1(chain "A" and (resid 2 through 31 or (resid 44...
d_1ens_2(chain "D" and (resid 1 through 22 or resid 33...
d_2ens_2(chain "B" and ((resid 1 and (name N or name...

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1ALAALALEULEUCC2 - 695 - 72
d_21ens_1ALAALAGLNGLNAA2 - 315 - 34
d_22ens_1ARGARGLEULEUAA44 - 6947 - 72
d_11ens_2GLUGLULYSLYSDD1 - 222 - 23
d_12ens_2THRTHRHISHISDD33 - 14834 - 149
d_21ens_2GLUGLUHISHISBB1 - 1052 - 106
d_22ens_2SERSERHISHISBB113 - 148114 - 149

NCS ensembles :
ID
ens_1
ens_2

NCS oper:
IDCodeMatrixVector
1given(0.706522890043, 0.0397608652989, 0.706572345507), (0.0508595580096, -0.998691521427, 0.00534325631532), (0.705860263228, 0.0321608243002, -0.707620640016)-12.8343152897, 21.1519307304, 29.0193432726
2given(0.712137765464, 0.042289675805, 0.700764858081), (0.0394790207295, -0.999016829615, 0.0201688142323), (0.700928819441, 0.0133025360592, -0.713107167691)-12.5179497528, 20.55452995, 29.4646204384

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Components

#1: Protein Sc-apCC-2-MCL-1-4


Mass: 8557.664 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others)
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
#2: Protein Induced myeloid leukemia cell differentiation protein Mcl-1


Mass: 17765.219 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Human MCL-1 from residue 172 to 327 / Source: (gene. exp.) Homo sapiens (human) / Gene: MCL1
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: Q07820
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationN

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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: 2.34 Å3/Da / Density % sol: 47.44 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1 M HEPES, 10% w/v PEG8000, 8% v/v ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.95 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: May 10, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95 Å / Relative weight: 1
ReflectionResolution: 2.8→58.34 Å / Num. obs: 12058 / % possible obs: 100 % / Redundancy: 7.1 % / Biso Wilson estimate: 44.68 Å2 / CC1/2: 1 / Net I/σ(I): 15.9
Reflection shellResolution: 2.8→2.95 Å / Num. unique obs: 1743 / CC1/2: 0.99

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Processing

Software
NameVersionClassification
PHENIX1.21_5207refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→58.34 Å / SU ML: 0.4019 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 34.7649
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2948 1114 4.75 %
Rwork0.2483 22340 -
obs0.2505 12024 99.79 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 60.82 Å2
Refinement stepCycle: LAST / Resolution: 2.8→58.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2918 0 0 4 2922
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00572951
X-RAY DIFFRACTIONf_angle_d0.89474004
X-RAY DIFFRACTIONf_chiral_restr0.0481494
X-RAY DIFFRACTIONf_plane_restr0.0069506
X-RAY DIFFRACTIONf_dihedral_angle_d21.6791003
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2CCX-RAY DIFFRACTIONTorsion NCS0.667270686094
ens_2d_2DDX-RAY DIFFRACTIONTorsion NCS0.573165811061
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-2.930.35991390.29742789X-RAY DIFFRACTION99.76
2.93-3.080.35151420.28642778X-RAY DIFFRACTION99.66
3.08-3.270.30191100.27792821X-RAY DIFFRACTION99.83
3.27-3.530.29461520.26982817X-RAY DIFFRACTION99.8
3.53-3.880.33341080.25632793X-RAY DIFFRACTION99.79
3.88-4.440.28511700.22752761X-RAY DIFFRACTION99.86
4.45-5.60.30221220.23922832X-RAY DIFFRACTION99.97
5.6-58.340.25011710.21862749X-RAY DIFFRACTION99.69
Refinement TLS params.Method: refined / Origin x: -4.59023734825 Å / Origin y: 10.3408392261 Å / Origin z: 14.8269812027 Å
111213212223313233
T0.553387036897 Å2-0.00469301286311 Å20.129163394535 Å2-0.422767988919 Å20.0209064183247 Å2--0.480185664477 Å2
L1.60286203587 °20.04597079446 °2-0.780458149119 °2-3.81752094156 °20.355741637144 °2--2.62908976971 °2
S-0.0318304326086 Å °-0.0172757823931 Å °-0.0100674431954 Å °0.217023460105 Å °0.0345235787549 Å °-0.197455796074 Å °-0.250642268426 Å °0.13694794874 Å °-0.0276064516507 Å °
Refinement TLS groupSelection details: all

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