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- PDB-5cp9: The structure of the NK1 fragment of HGF/SF complexed with MB605 -

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Basic information

Entry
Database: PDB / ID: 5cp9
TitleThe structure of the NK1 fragment of HGF/SF complexed with MB605
ComponentsHepatocyte growth factor
KeywordsHORMONE / HGF/SF / NK1 fragment / fragment based drug discovery / growth factor / cell cycle / new chemical entity
Function / homology
Function and homology information


regulation of p38MAPK cascade / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / Drug-mediated inhibition of MET activation / skeletal muscle cell proliferation / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins / MET Receptor Activation / hepatocyte growth factor receptor signaling pathway / MET receptor recycling ...regulation of p38MAPK cascade / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / Drug-mediated inhibition of MET activation / skeletal muscle cell proliferation / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins / MET Receptor Activation / hepatocyte growth factor receptor signaling pathway / MET receptor recycling / MET activates PTPN11 / MET activates RAP1 and RAC1 / myoblast proliferation / MET activates PI3K/AKT signaling / MET activates PTK2 signaling / positive regulation of DNA biosynthetic process / cellular response to hepatocyte growth factor stimulus / negative regulation of release of cytochrome c from mitochondria / negative regulation of peptidyl-serine phosphorylation / chemoattractant activity / negative regulation of interleukin-6 production / positive regulation of interleukin-10 production / epithelial to mesenchymal transition / positive regulation of osteoblast differentiation / MET activates RAS signaling / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / Interleukin-7 signaling / negative regulation of autophagy / liver development / cell chemotaxis / epithelial cell proliferation / platelet alpha granule lumen / growth factor activity / cell morphogenesis / Negative regulation of MET activity / negative regulation of inflammatory response / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / Platelet degranulation / mitotic cell cycle / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / Interleukin-4 and Interleukin-13 signaling / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cell migration / positive regulation of protein phosphorylation / signaling receptor binding / negative regulation of apoptotic process / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular region / identical protein binding / membrane
Similarity search - Function
Hepatocyte growth factor / Hepatocyte growth factor/Macrophage stimulatory protein / Hepatocyte Growth Factor / Hepatocyte Growth Factor / Plasminogen Kringle 4 / Plasminogen Kringle 4 / divergent subfamily of APPLE domains / : / PAN/Apple domain profile. / PAN domain ...Hepatocyte growth factor / Hepatocyte growth factor/Macrophage stimulatory protein / Hepatocyte Growth Factor / Hepatocyte Growth Factor / Plasminogen Kringle 4 / Plasminogen Kringle 4 / divergent subfamily of APPLE domains / : / PAN/Apple domain profile. / PAN domain / PAN/Apple domain / Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. / Kringle domain profile. / Kringle domain / Kringle-like fold / 3-Layer(bba) Sandwich / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
3-(furan-2-yl)propanoic acid / Hepatocyte growth factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsSigurdardottir, A.G. / Winter, A. / Sobkowicz, A. / Fragai, M. / Chirgadze, D.Y. / Ascher, D.B. / Blundell, T.L. / Gherardi, E.
CitationJournal: Chem Sci / Year: 2015
Title: Exploring the chemical space of the lysine-binding pocket of the first kringle domain of hepatocyte growth factor/scatter factor (HGF/SF) yields a new class of inhibitors of HGF/SF-MET binding.
Authors: Sigurdardottir, A.G. / Winter, A. / Sobkowicz, A. / Fragai, M. / Chirgadze, D. / Ascher, D.B. / Blundell, T.L. / Gherardi, E.
History
DepositionJul 21, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 12, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 26, 2016Group: Database references
Revision 1.2Aug 29, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI ..._citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.3Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Hepatocyte growth factor
B: Hepatocyte growth factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5474
Polymers42,3452
Non-polymers2022
Water4,216234
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2490 Å2
ΔGint-2 kcal/mol
Surface area17600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.387, 63.649, 57.198
Angle α, β, γ (deg.)90.00, 95.24, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Hepatocyte growth factor / Hepatopoietin-A / Scatter factor / SF


Mass: 21172.273 Da / Num. of mol.: 2 / Fragment: UNP residues 28-210 / Mutation: A29V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HGF, HPTA / Production host: Komagataella pastoris CBS 7435 (fungus) / References: UniProt: P14210
#2: Chemical ChemComp-6O5 / 3-(furan-2-yl)propanoic acid / MB605


Mass: 140.137 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H8O3
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 234 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.29 Å3/Da / Density % sol: 46.18 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 19% PEG 4000, 200 mM Na Acetate, 150 mM Tris / PH range: 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 27, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 30034 / % possible obs: 99.4 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.04 / Rsym value: 0.04 / Net I/σ(I): 20.1
Reflection shellResolution: 1.9→1.94 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.259 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1NK1

1nk1


Resolution: 1.9→26.58 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.942 / SU B: 3.211 / SU ML: 0.096 / Cross valid method: THROUGHOUT / ESU R: 0.162 / ESU R Free: 0.143 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.227 1524 5.1 %RANDOM
Rwork0.195 ---
obs0.196 28491 99.06 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 36.05 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å2-0 Å2-0 Å2
2---0 Å20 Å2
3---0 Å2
Refinement stepCycle: 1 / Resolution: 1.9→26.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2774 0 14 234 3022
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0222874
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1461.953869
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9725346
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.42423.594128
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.38815523
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.6941518
X-RAY DIFFRACTIONr_chiral_restr0.0790.2395
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212164
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_it2.03751732
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.12862809
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.71351142
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.2187.51060
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.898→1.947 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.25 109 -
Rwork0.234 1993 -
obs--94.98 %

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