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- PDB-3v5q: Discovery of a selective TRK Inhibitor with efficacy in rodent ca... -

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Basic information

Entry
Database: PDB / ID: 3v5q
TitleDiscovery of a selective TRK Inhibitor with efficacy in rodent cancer tumor models
ComponentsNT-3 growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase Domain / Kinase / Phosphorylation / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


axon extension involved in regeneration / NTF3 activates NTRK3 signaling / Activated NTRK3 signals through PLCG1 / positive regulation of axon extension involved in regeneration / Signaling by NTRK3 (TRKC) / postsynaptic density assembly / Receptor-type tyrosine-protein phosphatases / NTRK3 as a dependence receptor / neurotrophin receptor activity / mechanoreceptor differentiation ...axon extension involved in regeneration / NTF3 activates NTRK3 signaling / Activated NTRK3 signals through PLCG1 / positive regulation of axon extension involved in regeneration / Signaling by NTRK3 (TRKC) / postsynaptic density assembly / Receptor-type tyrosine-protein phosphatases / NTRK3 as a dependence receptor / neurotrophin receptor activity / mechanoreceptor differentiation / neuron fate specification / neurotrophin binding / lens fiber cell differentiation / regulation of neural precursor cell proliferation / myelination in peripheral nervous system / Activated NTRK3 signals through PI3K / neuronal action potential propagation / positive regulation of positive chemotaxis / positive regulation of synapse assembly / response to corticosterone / negative regulation of astrocyte differentiation / cochlea development / Activated NTRK3 signals through RAS / GPI-linked ephrin receptor activity / regulation of presynapse assembly / cellular response to retinoic acid / transmembrane receptor protein tyrosine kinase activity / cell surface receptor protein tyrosine kinase signaling pathway / cellular response to nerve growth factor stimulus / receptor protein-tyrosine kinase / positive regulation of neuron projection development / circadian rhythm / neuron migration / Constitutive Signaling by Aberrant PI3K in Cancer / p53 binding / PIP3 activates AKT signaling / heart development / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / response to ethanol / postsynaptic membrane / receptor complex / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of MAPK cascade / positive regulation of cell migration / positive regulation of apoptotic process / axon / positive regulation of cell population proliferation / positive regulation of gene expression / glutamatergic synapse / ATP binding / plasma membrane / cytoplasm
Similarity search - Function
NT-3 growth factor receptor NTRK3 / Growth factor receptor NTRK / Growth factor receptor NTRK, leucine rich repeat C-terminal / Leucine rich repeat C-terminal motif / Leucine rich repeat N-terminal domain / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Tyrosine-protein kinase, receptor class II, conserved site ...NT-3 growth factor receptor NTRK3 / Growth factor receptor NTRK / Growth factor receptor NTRK, leucine rich repeat C-terminal / Leucine rich repeat C-terminal motif / Leucine rich repeat N-terminal domain / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Immunoglobulin / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set domain / Leucine rich repeat / Leucine-rich repeat profile. / : / Leucine-rich repeat / Leucine-rich repeat domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Immunoglobulin-like 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-0F4 / NT-3 growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.2001 Å
AuthorsKreusch, A.
CitationJournal: ACS Med Chem Lett / Year: 2012
Title: Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models.
Authors: Albaugh, P. / Fan, Y. / Mi, Y. / Sun, F. / Adrian, F. / Li, N. / Jia, Y. / Sarkisova, Y. / Kreusch, A. / Hood, T. / Lu, M. / Liu, G. / Huang, S. / Liu, Z. / Loren, J. / Tuntland, T. / ...Authors: Albaugh, P. / Fan, Y. / Mi, Y. / Sun, F. / Adrian, F. / Li, N. / Jia, Y. / Sarkisova, Y. / Kreusch, A. / Hood, T. / Lu, M. / Liu, G. / Huang, S. / Liu, Z. / Loren, J. / Tuntland, T. / Karanewsky, D.S. / Seidel, H.M. / Molteni, V.
History
DepositionDec 16, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 8, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: NT-3 growth factor receptor
B: NT-3 growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,9235
Polymers67,8812
Non-polymers1,0423
Water3,405189
1
A: NT-3 growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4793
Polymers33,9401
Non-polymers5392
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: NT-3 growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4442
Polymers33,9401
Non-polymers5031
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)65.580, 65.580, 177.252
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number145
Space group name H-MP32

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Components

#1: Protein NT-3 growth factor receptor / GP145-TrkC / Trk-C / Neurotrophic tyrosine kinase receptor type 3 / TrkC tyrosine kinase


Mass: 33940.492 Da / Num. of mol.: 2 / Fragment: Kinase Domain (UNP Residues 530-818)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NTRK3, TRKC / Plasmid: pFastBac / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9
References: UniProt: Q16288, receptor protein-tyrosine kinase
#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-0F4 / 1-(3-{[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-6-yl]amino}phenyl)-3-[3-(trifluoromethyl)phenyl]urea


Mass: 503.475 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H20F3N5O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 189 / 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: 3.29 Å3/Da / Density % sol: 62.66 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.2
Details: 2.5 M NaCl, 0.1 M Na/K phosphate, pH 6.2, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 27, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.19→50 Å / Num. obs: 37248 / % possible obs: 84.5 % / Redundancy: 1.6 % / Rmerge(I) obs: 0.076 / Χ2: 2.192 / Net I/σ(I): 10.5
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.19-2.271.50.43629151.046166.1
2.27-2.361.50.33532821.245175.3
2.36-2.471.60.27439991.371190.3
2.47-2.61.60.24236961.735183.6
2.6-2.761.60.17138311.973186.8
2.76-2.971.60.1338742.22188.5
2.97-3.271.60.10139172.997188.2
3.27-3.741.70.0838533.046188
3.74-4.721.80.06440142.916190.4
4.72-501.80.05438672.199187.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
MOLREPphasing
PHENIX1.7.2_869refinement
PDB_EXTRACT3.1data extraction
HKL-2000data collection
DENZOdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2001→40.945 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.85 / σ(F): 1.97 / Phase error: 28.17 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2635 1865 5.06 %
Rwork0.2118 --
obs0.2144 36886 85.2 %
Solvent computationShrinkage radii: 0.98 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 67.795 Å2 / ksol: 0.4 e/Å3
Displacement parametersBiso max: 90.26 Å2 / Biso mean: 45.3129 Å2 / Biso min: 19.96 Å2
Baniso -1Baniso -2Baniso -3
1-1.8337 Å2-0 Å2-0 Å2
2--1.8337 Å2-0 Å2
3----3.6674 Å2
Refinement stepCycle: LAST / Resolution: 2.2001→40.945 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4216 0 75 189 4480
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084406
X-RAY DIFFRACTIONf_angle_d1.3685960
X-RAY DIFFRACTIONf_chiral_restr0.077652
X-RAY DIFFRACTIONf_plane_restr0.005737
X-RAY DIFFRACTIONf_dihedral_angle_d19.5451594
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.2001-2.25950.36871310.31062196232770
2.2595-2.3260.34861490.29892333248274
2.326-2.40110.33681310.27922669280084
2.4011-2.48690.34931460.27912794294088
2.4869-2.58650.35531350.26132647278284
2.5865-2.70410.2691690.23922844301389
2.7041-2.84670.3191420.242763290587
2.8467-3.0250.32891410.23172667280886
3.025-3.25850.27231550.19962865302090
3.2585-3.58620.22131340.18952826296090
3.5862-4.10470.23371320.17912869300189
4.1047-5.16990.20851620.17062795295790
5.1699-40.95210.26111380.2252753289187

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