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- PDB-9c1r: Crystal structure of mutant cMET D1228N kinase domain in complex ... -

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Basic information

Entry
Database: PDB / ID: 9c1r
TitleCrystal structure of mutant cMET D1228N kinase domain in complex with inhibitor compound 13
ComponentsHepatocyte growth factor receptor
KeywordsSIGNALING PROTEIN / cMET Kinase domain
Function / homology
Function and homology information


negative regulation of guanyl-nucleotide exchange factor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET Receptor Activation / MET interacts with TNS proteins / endothelial cell morphogenesis / semaphorin receptor activity / MET receptor recycling / pancreas development ...negative regulation of guanyl-nucleotide exchange factor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET Receptor Activation / MET interacts with TNS proteins / endothelial cell morphogenesis / semaphorin receptor activity / MET receptor recycling / pancreas development / MET activates PTPN11 / MET activates RAP1 and RAC1 / Sema4D mediated inhibition of cell attachment and migration / MET activates PI3K/AKT signaling / negative regulation of stress fiber assembly / positive regulation of endothelial cell chemotaxis / MET activates PTK2 signaling / branching morphogenesis of an epithelial tube / positive chemotaxis / negative regulation of Rho protein signal transduction / negative regulation of thrombin-activated receptor signaling pathway / semaphorin-plexin signaling pathway / establishment of skin barrier / MET activates RAS signaling / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / MECP2 regulates neuronal receptors and channels / positive regulation of microtubule polymerization / negative regulation of autophagy / cell surface receptor protein tyrosine kinase signaling pathway / liver development / molecular function activator activity / InlB-mediated entry of Listeria monocytogenes into host cell / basal plasma membrane / excitatory postsynaptic potential / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / Negative regulation of MET activity / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / protein phosphatase binding / receptor complex / cell surface receptor signaling pathway / postsynapse / cell surface / signal transduction / positive regulation of transcription by RNA polymerase II / extracellular region / ATP binding / identical protein binding / membrane / 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 / IPT domain / PSI domain / domain found in Plexins, Semaphorins and Integrins / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Immunoglobulin E-set / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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
: / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.59 Å
AuthorsSimpson, H. / Wu, W.-I. / Mou, T.-C.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of Pyrazolopyrazines as Selective, Potent, and Mutant-Active MET Inhibitors with Intracranial Efficacy.
Authors: Bumpers, Q.A. / Pipal, R.W. / Benz-Weeden, A.M. / Brewster 2nd, J.T. / Cook, A. / Crooks, A.L. / Cruz, C. / Dwulet, N.C. / Gaudino, J.J. / Golec, D. / Harrison, J.A. / Hartley, D.P. / ...Authors: Bumpers, Q.A. / Pipal, R.W. / Benz-Weeden, A.M. / Brewster 2nd, J.T. / Cook, A. / Crooks, A.L. / Cruz, C. / Dwulet, N.C. / Gaudino, J.J. / Golec, D. / Harrison, J.A. / Hartley, D.P. / Hassanien, S.H. / Hicken, E.J. / Kahn, D. / Laird, E.R. / Lemieux, C. / Lewandowski, N. / McCown, J. / McDonald, M.G. / McNulty, O. / Mou, T.C. / Nguyen, P. / Oko, L. / Opie, L.P. / Otten, J. / Peck, S.C. / Polites, V.C. / Randall, S.D. / Rosen, R.Z. / Savechenkov, P. / Simpson, H. / Singh, A. / Sparks, D. / Wickersham, K. / Wollenberg, L. / Wong, C.E. / Wong, J. / Wu, W.I. / Elsayed, M.S.A. / Hinklin, R.J. / Tang, T.P.
History
DepositionMay 29, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 21, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6503
Polymers34,9451
Non-polymers7052
Water5,260292
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1370 Å2
ΔGint-8 kcal/mol
Surface area14300 Å2
Unit cell
Length a, b, c (Å)38.604, 62.248, 113.285
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Hepatocyte growth factor receptor / 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: 34945.473 Da / Num. of mol.: 1 / Fragment: UNP Residues 1048-1348 / Mutation: D1228N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Production host: unidentified baculovirus
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-A1ATS / N-(2,5-difluoro-4-{[(1s,3S)-3-(1-methyl-1H-pyrazol-3-yl)cyclobutyl][(8R)-pyrazolo[1,5-a]pyrazin-4-yl]amino}phenyl)-2-(5-fluoropyridin-2-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide


Mass: 612.565 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H23F3N10O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 292 / 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: 1.95 Å3/Da / Density % sol: 36.84 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 22% PEG 3350 0.1M Bis-Tris pH6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-X / Wavelength: 1.54 Å
DetectorType: DECTRIS EIGER R 4M / Detector: PIXEL / Date: Jul 13, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.59→27.28 Å / Num. obs: 37674 / % possible obs: 100 % / Redundancy: 9.2 % / Biso Wilson estimate: 12.31 Å2 / CC1/2: 0.998 / Rpim(I) all: 0.039 / Rrim(I) all: 0.123 / Net I/σ(I): 11
Reflection shellResolution: 1.59→1.647 Å / Redundancy: 5.2 % / Mean I/σ(I) obs: 2.2 / Num. unique obs: 1859 / CC1/2: 0.893 / Rpim(I) all: 0.24 / Rrim(I) all: 0.567

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHENIX1.20.1_4487refinement
CrysalisProdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.59→27.28 Å / SU ML: 0.1137 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 17.407
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1947 2000 5.31 %
Rwork0.1686 35663 -
obs0.17 37663 99.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 15.86 Å2
Refinement stepCycle: LAST / Resolution: 1.59→27.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2263 0 51 292 2606
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00452531
X-RAY DIFFRACTIONf_angle_d0.79013460
X-RAY DIFFRACTIONf_chiral_restr0.0513378
X-RAY DIFFRACTIONf_plane_restr0.0072444
X-RAY DIFFRACTIONf_dihedral_angle_d7.0635346
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.59-1.630.2311400.21042508X-RAY DIFFRACTION99.85
1.63-1.670.22911410.2022506X-RAY DIFFRACTION99.96
1.67-1.720.20041400.18992488X-RAY DIFFRACTION100
1.72-1.780.24141420.1882539X-RAY DIFFRACTION100
1.78-1.840.19761410.17842515X-RAY DIFFRACTION99.89
1.84-1.910.21081410.17342494X-RAY DIFFRACTION99.92
1.91-20.20871410.16482529X-RAY DIFFRACTION100
2-2.110.16181420.16242544X-RAY DIFFRACTION100
2.11-2.240.19621420.16072522X-RAY DIFFRACTION100
2.24-2.410.21761430.15742561X-RAY DIFFRACTION100
2.41-2.650.19541420.16972534X-RAY DIFFRACTION100
2.65-3.040.15581450.16752581X-RAY DIFFRACTION100
3.04-3.820.19181460.15452613X-RAY DIFFRACTION100
3.83-27.280.19211540.16752729X-RAY DIFFRACTION99.65
Refinement TLS params.Method: refined / Origin x: -9.79158283021 Å / Origin y: -4.56800683521 Å / Origin z: 15.1726893468 Å
111213212223313233
T0.0729855790191 Å20.00406403854297 Å2-0.00532299355012 Å2-0.0889964675402 Å2-0.0052258747136 Å2--0.0841725745748 Å2
L0.224992482074 °2-0.0578095836527 °20.0464289068493 °2-0.566176469193 °2-0.317692707832 °2--0.411123212738 °2
S0.0048201052571 Å °0.0107741002472 Å °-0.0145241753997 Å °-0.00900081272695 Å °0.00441439643389 Å °0.000606152013235 Å °-0.00162808495976 Å °0.00728998346517 Å °-0.00937449863198 Å °
Refinement TLS groupSelection details: all

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