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- PDB-7b43: Crystal structure of c-MET bound by compound 9 -

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Basic information

Entry
Database: PDB / ID: 7b43
TitleCrystal structure of c-MET bound by compound 9
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE / c-met / kinase / folded P-loop / inhibitor
Function / homology
Function and homology information


hepatocyte growth factor receptor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / endothelial cell morphogenesis / negative regulation of hydrogen peroxide-mediated programmed cell death / negative regulation of guanyl-nucleotide exchange factor activity / MET interacts with TNS proteins / MET Receptor Activation / positive regulation of endothelial cell chemotaxis / semaphorin receptor activity ...hepatocyte growth factor receptor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / endothelial cell morphogenesis / negative regulation of hydrogen peroxide-mediated programmed cell death / negative regulation of guanyl-nucleotide exchange factor activity / MET interacts with TNS proteins / MET Receptor Activation / positive regulation of endothelial cell chemotaxis / semaphorin receptor activity / MET receptor recycling / Sema4D mediated inhibition of cell attachment and migration / MET activates PTPN11 / pancreas development / MET activates RAP1 and RAC1 / MET activates PI3K/AKT signaling / negative regulation of Rho protein signal transduction / negative regulation of stress fiber assembly / semaphorin-plexin signaling pathway / MET activates PTK2 signaling / negative regulation of thrombin-activated receptor signaling pathway / branching morphogenesis of an epithelial tube / positive chemotaxis / establishment of skin barrier / MET activates RAS signaling / MECP2 regulates neuronal receptors and channels / phagocytosis / positive regulation of microtubule polymerization / negative regulation of autophagy / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / liver development / molecular function activator activity / neuron differentiation / Negative regulation of MET activity / receptor protein-tyrosine kinase / transmembrane receptor protein tyrosine kinase activity / positive regulation of kinase activity / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / nervous system development / transmembrane receptor protein tyrosine kinase signaling pathway / cell migration / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein phosphatase binding / protein tyrosine kinase activity / positive regulation of protein kinase B signaling / cell surface receptor signaling pathway / receptor complex / cell surface / signal transduction / positive regulation of transcription by RNA polymerase II / extracellular region / ATP binding / membrane / identical protein binding / plasma membrane
Similarity search - Function
Tyrosine-protein kinase, HGF/MSP receptor / Plexin family / Plexin repeat / Plexin repeat / Sema domain / semaphorin domain / Sema domain / Sema domain superfamily / Sema domain profile. / IPT/TIG domain ...Tyrosine-protein kinase, HGF/MSP receptor / Plexin family / Plexin repeat / Plexin repeat / Sema domain / semaphorin domain / Sema domain / Sema domain superfamily / Sema domain profile. / IPT/TIG domain / ig-like, plexins, transcription factors / PSI domain / domain found in Plexins, Semaphorins and Integrins / IPT domain / Immunoglobulin E-set / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-SW5 / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.87 Å
AuthorsCollie, G.W.
CitationJournal: Acs Med.Chem.Lett. / Year: 2021
Title: Structural Basis for Targeting the Folded P-Loop Conformation of c-MET.
Authors: Collie, G.W. / Michaelides, I.N. / Embrey, K. / Stubbs, C.J. / Borjesson, U. / Dale, I.L. / Snijder, A. / Barlind, L. / Song, K. / Khurana, P. / Phillips, C. / Storer, R.I.
History
DepositionDec 2, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 9, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 23, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.title / _citation.year
Revision 1.2Feb 3, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)68,3234
Polymers67,5722
Non-polymers7512
Water2,306128
1
A: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,1622
Polymers33,7861
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,1622
Polymers33,7861
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.867, 59.738, 77.603
Angle α, β, γ (deg.)76.510, 73.880, 69.250
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Hepatocyte growth factor receptor / C-Met / HGF receptor / HGF/SF receptor / Proto-oncogene c-Met / Scatter factor receptor / SF receptor / ...HGF receptor / HGF/SF receptor / Proto-oncogene c-Met / Scatter factor receptor / SF receptor / Tyrosine-protein kinase Met


Mass: 33786.207 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Production host: Escherichia coli (E. coli)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-SW5 / 3-[(4-fluorophenyl)methyl]-5-(1-piperidin-4-ylpyrazol-4-yl)-1~{H}-pyrrolo[2,3-b]pyridine


Mass: 375.442 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H22FN5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 128 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.61 Å3/Da / Density % sol: 52.91 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 28 % PEGMME2000, 0.1 M bis-tris pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00001 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Sep 17, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00001 Å / Relative weight: 1
ReflectionResolution: 1.87→73.706 Å / Num. obs: 28964 / % possible obs: 70 % / Redundancy: 2.7 % / Biso Wilson estimate: 24.8 Å2 / CC1/2: 0.985 / Rmerge(I) obs: 0.109 / Rpim(I) all: 0.08 / Rrim(I) all: 0.136 / Net I/σ(I): 3.8
Reflection shellResolution: 1.873→2.023 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.512 / Num. unique obs: 1449 / CC1/2: 0.741 / Rpim(I) all: 0.382 / Rrim(I) all: 0.642 / % possible all: 34.6

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Processing

Software
NameVersionClassification
Aimlessdata scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal

Resolution: 1.87→18.41 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.871 / SU R Cruickshank DPI: 0.298 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.278 / SU Rfree Blow DPI: 0.219 / SU Rfree Cruickshank DPI: 0.227
RfactorNum. reflection% reflectionSelection details
Rfree0.248 1384 4.79 %RANDOM
Rwork0.2 ---
obs0.203 28882 51.4 %-
Displacement parametersBiso max: 97.47 Å2 / Biso mean: 27.59 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1--0.9854 Å2-0.1181 Å2-0.2994 Å2
2--0.3223 Å20.2012 Å2
3---0.6632 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: final / Resolution: 1.87→18.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4307 0 56 128 4491
Biso mean--29.57 27.38 -
Num. residues----555
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1478SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes729HARMONIC5
X-RAY DIFFRACTIONt_it4481HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion574SEMIHARMONIC5
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_contact5266SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4481HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6092HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion2.66
X-RAY DIFFRACTIONt_other_torsion18.23
LS refinement shellResolution: 1.87→1.96 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2864 29 5.02 %
Rwork0.2199 549 -
all0.2236 578 -
obs--8.14 %

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