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- PDB-5amn: The Discovery of 2-Substituted Phenol Quinazolines as Potent and ... -

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Basic information

Entry
Database: PDB / ID: 5amn
TitleThe Discovery of 2-Substituted Phenol Quinazolines as Potent and Selective RET Kinase Inhibitors
ComponentsPROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET
KeywordsTRANSFERASE / RET / ONCOGENE / RECEPTOR TYROSINE KINASE / CHEMICAL INHIBITOR / CANCER
Function / homology
Function and homology information


Peyer's patch morphogenesis / GDF15-GFRAL signaling pathway / positive regulation of metanephric glomerulus development / ureter maturation / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / posterior midgut development / membrane protein proteolysis / Formation of the ureteric bud ...Peyer's patch morphogenesis / GDF15-GFRAL signaling pathway / positive regulation of metanephric glomerulus development / ureter maturation / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / posterior midgut development / membrane protein proteolysis / Formation of the ureteric bud / positive regulation of neuron maturation / neuron cell-cell adhesion / Formation of the nephric duct / enteric nervous system development / innervation / plasma membrane protein complex / neuron maturation / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of cell adhesion mediated by integrin / neural crest cell migration / ureteric bud development / regulation of axonogenesis / response to pain / homophilic cell adhesion via plasma membrane adhesion molecules / RET signaling / positive regulation of cell size / regulation of cell adhesion / cellular response to retinoic acid / transmembrane receptor protein tyrosine kinase activity / NPAS4 regulates expression of target genes / axon guidance / cell surface receptor protein tyrosine kinase signaling pathway / 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 / positive regulation of neuron projection development / MAPK cascade / signaling receptor activity / retina development in camera-type eye / RAF/MAP kinase cascade / protein tyrosine kinase activity / early endosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of MAPK cascade / endosome membrane / positive regulation of cell migration / protein phosphorylation / response to xenobiotic stimulus / axon / neuronal cell body / dendrite / calcium ion binding / positive regulation of gene expression / positive regulation of DNA-templated transcription / signal transduction / ATP binding / plasma membrane
Similarity search - Function
Tyrosine-protein kinase, Ret receptor / Tyrosine-protein kinase receptor Ret, cadherin like domain 3 / Ret, cadherin like domain 1 / RET, cadherin-like domain 4 / : / RET Cadherin like domain 1 / RET Cadherin like domain 3 / RET Cadherin like domain 4 / RET, Cysteine Rich Domain / Cadherin domain ...Tyrosine-protein kinase, Ret receptor / Tyrosine-protein kinase receptor Ret, cadherin like domain 3 / Ret, cadherin like domain 1 / RET, cadherin-like domain 4 / : / RET Cadherin like domain 1 / RET Cadherin like domain 3 / RET Cadherin like domain 4 / RET, Cysteine Rich Domain / Cadherin domain / Cadherin-like / Cadherins domain profile. / Cadherin-like superfamily / : / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / 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
4-[3-HYDROXYANILINO]-6,7-DIMETHOXYQUINAZOLINE / FORMIC ACID / Proto-oncogene tyrosine-protein kinase receptor Ret
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.57 Å
AuthorsNewton, R. / Bowler, K. / Burns, E.M. / Chapman, P. / Fairweather, E. / Fritzl, S. / Goldberg, K. / Hamilton, N.M. / Holt, S.V. / Hopkins, G.V. ...Newton, R. / Bowler, K. / Burns, E.M. / Chapman, P. / Fairweather, E. / Fritzl, S. / Goldberg, K. / Hamilton, N.M. / Holt, S.V. / Hopkins, G.V. / Jones, S.D. / Jordan, A.M. / Lyons, A. / McDonald, N.Q. / Maguire, L.A. / Mould, D.P. / Purkiss, A.G. / Small, H.F. / Stowell, A. / Thomson, G.J. / Waddell, I.D. / Waszkowycz, B. / Watson, A.J. / Ogilvie, D.J.
CitationJournal: Eur J Med Chem / Year: 2016
Title: The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity.
Authors: Newton, R. / Bowler, K.A. / Burns, E.M. / Chapman, P.J. / Fairweather, E.E. / Fritzl, S.J.R. / Goldberg, K.M. / Hamilton, N.M. / Holt, S.V. / Hopkins, G.V. / Jones, S.D. / Jordan, A.M. / ...Authors: Newton, R. / Bowler, K.A. / Burns, E.M. / Chapman, P.J. / Fairweather, E.E. / Fritzl, S.J.R. / Goldberg, K.M. / Hamilton, N.M. / Holt, S.V. / Hopkins, G.V. / Jones, S.D. / Jordan, A.M. / Lyons, A.J. / Nikki March, H. / McDonald, N.Q. / Maguire, L.A. / Mould, D.P. / Purkiss, A.G. / Small, H.F. / Stowell, A.I.J. / Thomson, G.J. / Waddell, I.D. / Waszkowycz, B. / Watson, A.J. / Ogilvie, D.J.
History
DepositionMar 11, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 17, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 2, 2016Group: Database references
Revision 1.2Feb 28, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation_author.name
Revision 1.3Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9739
Polymers34,3541
Non-polymers6198
Water86548
1
A: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET
hetero molecules

A: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,94618
Polymers68,7072
Non-polymers1,23916
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_735y+2,x-2,-z1
Buried area6870 Å2
ΔGint-17.6 kcal/mol
Surface area24620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.570, 50.570, 242.840
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET / CADHERIN FAMILY MEMBER 12 / PROTO-ONCOGENE C-RET


Mass: 34353.613 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 705-826,841-1012
Source method: isolated from a genetically manipulated source
Details: PHOSPHORYLATION AT Y900 AND Y905 / Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P07949, receptor protein-tyrosine kinase
#2: Chemical ChemComp-DTQ / 4-[3-HYDROXYANILINO]-6,7-DIMETHOXYQUINAZOLINE


Mass: 297.309 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H15N3O3
#3: Chemical
ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: CH2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 48 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Nonpolymer detailsPHOSPHOTYROSINE (PTR): PHOSPHORYLATION OF TYROSINE RESIDUES FORMIC ACID (FMT): PRESENT AS FORMATE.
Sequence detailsRESIDUES 827-840 HAVE BEEN DELETED FROM THE CONSTRUCT

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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: 2.31 Å3/Da / Density % sol: 46.7 %
Description: MOLECULAR REPLACEMENT USED N- AND C-LOBES SEPARATELY.
Crystal growpH: 4.4 / Details: 3.4M SODIUM FORMATE 0.1M SODIUM ACETATE PH 4.4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 23, 2014 / Details: MIRRORS
RadiationMonochromator: DOUBLE CRYSTAL SILICON / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.57→60.73 Å / Num. obs: 10852 / % possible obs: 99.9 % / Observed criterion σ(I): 1 / Redundancy: 13.6 % / Biso Wilson estimate: 36.66 Å2 / Rmerge(I) obs: 0.2 / Net I/σ(I): 11.4
Reflection shellResolution: 2.57→2.64 Å / Redundancy: 14.5 % / Rmerge(I) obs: 0.9 / Mean I/σ(I) obs: 3.3 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3TXO

3txo


Resolution: 2.57→60.71 Å / SU ML: 0.26 / σ(F): 1.36 / Phase error: 23.1 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2371 551 5.1 %
Rwork0.183 --
obs0.1858 10852 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 35.69 Å2
Refinement stepCycle: LAST / Resolution: 2.57→60.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2219 0 43 48 2310
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032308
X-RAY DIFFRACTIONf_angle_d0.6213119
X-RAY DIFFRACTIONf_dihedral_angle_d12.878859
X-RAY DIFFRACTIONf_chiral_restr0.025342
X-RAY DIFFRACTIONf_plane_restr0.002390
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.57-2.82860.31851300.22252491X-RAY DIFFRACTION100
2.8286-3.23790.29731520.21132496X-RAY DIFFRACTION100
3.2379-4.07930.21691180.17042563X-RAY DIFFRACTION100
4.0793-60.72690.19821510.16772751X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
16.245.66442.54827.85934.35542.57560.19890.74141.2697-0.5955-0.82460.8231-0.8957-0.90150.63060.43660.0671-0.02170.390.02920.332154.8606-21.5725-3.9999
20.58210.78740.30663.81750.56362.1703-0.05520.0634-0.0188-0.02760.01170.1845-0.0558-0.03640.0480.21480.0310.03230.22250.01420.303567.4777-9.95516.9729
31.9141-0.65440.12914.14030.36792.0075-0.0586-0.1379-0.06590.3148-0.0079-0.04330.1007-0.03370.06060.2513-0.0218-0.00120.22660.01960.210373.9033-28.511820.5889
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN 'A' AND (RESID 700 THROUGH 710)
2X-RAY DIFFRACTION2CHAIN 'A' AND (RESID 714 THROUGH 819)
3X-RAY DIFFRACTION3CHAIN 'A' AND (RESID 846 THROUGH 1009 )

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