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- PDB-3lkj: Small Molecule Inhibition of the TNF Family Cyokine CD40 Ligand T... -

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Basic information

Entry
Database: PDB / ID: 3lkj
TitleSmall Molecule Inhibition of the TNF Family Cyokine CD40 Ligand Through a Subunit Fracture Mechanism
ComponentsCD40 ligand
KeywordsCYTOKINE / CD40L / CD154 / TNF-family cytokine / protein-protein interaction / Cell membrane / Disease mutation / Disulfide bond / Glycoprotein / Membrane / Phosphoprotein / Secreted / Signal-anchor / Transmembrane
Function / homology
Function and homology information


CD40 receptor binding / CD40 signaling pathway / TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway / regulation of immunoglobulin production / positive regulation of endothelial cell apoptotic process / isotype switching / tumor necrosis factor receptor binding / leukocyte cell-cell adhesion / positive regulation of interleukin-4 production / B cell proliferation ...CD40 receptor binding / CD40 signaling pathway / TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway / regulation of immunoglobulin production / positive regulation of endothelial cell apoptotic process / isotype switching / tumor necrosis factor receptor binding / leukocyte cell-cell adhesion / positive regulation of interleukin-4 production / B cell proliferation / positive regulation of interleukin-10 production / positive regulation of T cell proliferation / T cell costimulation / positive regulation of interleukin-12 production / B cell differentiation / protein serine/threonine kinase activator activity / integrin-mediated signaling pathway / cytokine activity / TNFR2 non-canonical NF-kB pathway / platelet activation / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / integrin binding / positive regulation of NF-kappaB transcription factor activity / inflammatory response / external side of plasma membrane / negative regulation of apoptotic process / Golgi apparatus / cell surface / extracellular space / membrane / plasma membrane
Similarity search - Function
CD40 ligand / Tumour necrosis factor, conserved site / Tumor necrosis factor (TNF) homology domain (THD) signature. / Tumour necrosis factor family. / TNF(Tumour Necrosis Factor) family / Tumour necrosis factor domain / Tumor necrosis factor (TNF) homology domain (THD) profile. / Jelly Rolls - #40 / Tumour necrosis factor-like domain superfamily / Jelly Rolls ...CD40 ligand / Tumour necrosis factor, conserved site / Tumor necrosis factor (TNF) homology domain (THD) signature. / Tumour necrosis factor family. / TNF(Tumour Necrosis Factor) family / Tumour necrosis factor domain / Tumor necrosis factor (TNF) homology domain (THD) profile. / Jelly Rolls - #40 / Tumour necrosis factor-like domain superfamily / Jelly Rolls / Sandwich / Mainly Beta
Similarity search - Domain/homology
Chem-LKJ / CD40 ligand
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsSilvian, L.F. / Whitty, A.
CitationJournal: Acs Chem.Biol. / Year: 2011
Title: Small Molecule Inhibition of the TNF Family Cytokine CD40 Ligand through a Subunit Fracture Mechanism.
Authors: Silvian, L.F. / Friedman, J.E. / Strauch, K. / Cachero, T.G. / Day, E.S. / Qian, F. / Cunningham, B. / Fung, A. / Sun, L. / Su, L. / Zheng, Z. / Kumaravel, G. / Whitty, A.
History
DepositionJan 27, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 2, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jul 29, 2020Group: Advisory / Data collection ...Advisory / Data collection / Derived calculations / Structure summary
Category: chem_comp / database_PDB_caveat ...chem_comp / database_PDB_caveat / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.3Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _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: CD40 ligand
B: CD40 ligand
C: CD40 ligand
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,13610
Polymers45,9043
Non-polymers2,2327
Water1,29772
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6750 Å2
ΔGint4 kcal/mol
Surface area17490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.303, 67.607, 108.534
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein CD40 ligand / CD40-L / Tumor necrosis factor ligand superfamily member 5 / TNF-related activation protein / TRAP ...CD40-L / Tumor necrosis factor ligand superfamily member 5 / TNF-related activation protein / TRAP / T-cell antigen Gp39 / CD40 ligand / membrane form / CD40 ligand / soluble form


Mass: 15301.329 Da / Num. of mol.: 3 / Fragment: UNP residues 121-261
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD40L, CD40LG, TNFSF5, TRAP / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P29965
#2: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#3: Chemical ChemComp-LKJ / (2R)-{[(2'-[(biphenyl-3-ylmethyl)carbamoyl]-6'-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}-6-{[(2R)-2-(1H-pyrrol-1-ylmethyl)pyrrolidin-1-yl]carbonyl}-4,4'-bipyridin-2-yl)carbonyl]amino}(cyclohexyl)ethanoic acid


Mass: 905.093 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C53H60N8O6
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 72 / 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: 2.53 Å3/Da / Density % sol: 51.38 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 24% Peg3350, 50mM Hepes pH 7.5, 0.2M Sodium Citrate, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X25 / Wavelength: 0.99 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 19, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. all: 16534 / Num. obs: 16300 / % possible obs: 98.5 % / Observed criterion σ(I): 2 / Redundancy: 4 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 30.7
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.157 / Mean I/σ(I) obs: 5.8 / Num. unique all: 1447 / % possible all: 98.5

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
AMoREphasing
REFMAC5.5.0088refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ID 1ALY

1aly


Resolution: 2.5→28.69 Å / Cor.coef. Fo:Fc: 0.92 / Cor.coef. Fo:Fc free: 0.874 / SU B: 11.551 / SU ML: 0.263 / Cross valid method: THROUGHOUT / ESU R: 0.633 / ESU R Free: 0.355 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.30509 853 5.2 %RANDOM
Rwork0.22604 ---
obs0.23016 15596 98.62 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 36.137 Å2
Baniso -1Baniso -2Baniso -3
1--0.04 Å20 Å20 Å2
2---0.07 Å20 Å2
3---0.11 Å2
Refinement stepCycle: LAST / Resolution: 2.5→28.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3003 0 151 72 3226
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0223225
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.9722.0024374
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5765385
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.24724.113124
X-RAY DIFFRACTIONr_dihedral_angle_3_deg22.29715493
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.3131512
X-RAY DIFFRACTIONr_chiral_restr0.1510.2508
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212381
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.9851.51946
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.83923118
X-RAY DIFFRACTIONr_scbond_it2.21531279
X-RAY DIFFRACTIONr_scangle_it3.6654.51256
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.5→2.565 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.396 56 -
Rwork0.281 1047 -
obs--91.99 %

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