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- PDB-8stg: Discovery and clinical validation of RLY-4008, the first highly s... -

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Basic information

Entry
Database: PDB / ID: 8stg
TitleDiscovery and clinical validation of RLY-4008, the first highly selective FGFR2 inhibitor with activity across FGFR2 alterations and resistance mutations
ComponentsFibroblast growth factor receptor 2
KeywordsTRANSFERASE/INHIBITOR / Relay Inhibitor / CYTOSOLIC PROTEIN / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


Signaling by FGFR2 amplification mutants / Signaling by FGFR2 fusions / fibroblast growth factor receptor signaling pathway involved in negative regulation of apoptotic process in bone marrow cell / fibroblast growth factor receptor signaling pathway involved in hemopoiesis / fibroblast growth factor receptor signaling pathway involved in positive regulation of cell proliferation in bone marrow / lateral sprouting from an epithelium / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung development ...Signaling by FGFR2 amplification mutants / Signaling by FGFR2 fusions / fibroblast growth factor receptor signaling pathway involved in negative regulation of apoptotic process in bone marrow cell / fibroblast growth factor receptor signaling pathway involved in hemopoiesis / fibroblast growth factor receptor signaling pathway involved in positive regulation of cell proliferation in bone marrow / lateral sprouting from an epithelium / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung development / lacrimal gland development / prostate gland morphogenesis / otic vesicle formation / regulation of smooth muscle cell differentiation / regulation of morphogenesis of a branching structure / orbitofrontal cortex development / squamous basal epithelial stem cell differentiation involved in prostate gland acinus development / embryonic organ morphogenesis / branching morphogenesis of a nerve / endochondral bone growth / morphogenesis of embryonic epithelium / bud elongation involved in lung branching / epidermis morphogenesis / positive regulation of epithelial cell proliferation involved in lung morphogenesis / reproductive structure development / limb bud formation / membranous septum morphogenesis / lung lobe morphogenesis / gland morphogenesis / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / embryonic digestive tract morphogenesis / mesenchymal cell differentiation / epithelial cell proliferation involved in salivary gland morphogenesis / branching involved in labyrinthine layer morphogenesis / mesenchymal cell proliferation involved in lung development / pyramidal neuron development / branching involved in prostate gland morphogenesis / FGFR2b ligand binding and activation / FGFR2c ligand binding and activation / Activated point mutants of FGFR2 / Phospholipase C-mediated cascade; FGFR2 / regulation of osteoblast proliferation / branching involved in salivary gland morphogenesis / embryonic pattern specification / positive regulation of phospholipase activity / lung-associated mesenchyme development / outflow tract septum morphogenesis / regulation of smoothened signaling pathway / embryonic cranial skeleton morphogenesis / mesodermal cell differentiation / bone morphogenesis / digestive tract development / skeletal system morphogenesis / odontogenesis / positive regulation of mesenchymal cell proliferation / ureteric bud development / inner ear morphogenesis / organ growth / hair follicle morphogenesis / Signaling by FGFR2 IIIa TM / ventricular cardiac muscle tissue morphogenesis / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / regulation of osteoblast differentiation / PI-3K cascade:FGFR2 / lung alveolus development / prostate epithelial cord elongation / midbrain development / bone mineralization / fibroblast growth factor binding / positive regulation of cell division / excitatory synapse / PI3K Cascade / positive regulation of Wnt signaling pathway / cell fate commitment / fibroblast growth factor receptor signaling pathway / epithelial to mesenchymal transition / negative regulation of keratinocyte proliferation / embryonic organ development / regulation of ERK1 and ERK2 cascade / SHC-mediated cascade:FGFR2 / positive regulation of cardiac muscle cell proliferation / cellular response to transforming growth factor beta stimulus / FRS-mediated FGFR2 signaling / cellular response to retinoic acid / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of cell cycle / Signaling by FGFR2 in disease / epithelial cell differentiation / axonogenesis / positive regulation of epithelial cell proliferation / post-embryonic development / animal organ morphogenesis / Negative regulation of FGFR2 signaling / lung development / 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
Similarity search - Function
Fibroblast growth factor receptor family / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set domain / : / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. ...Fibroblast growth factor receptor family / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set domain / : / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Ig-like domain profile. / Immunoglobulin-like domain / Transferase(Phosphotransferase) domain 1 / Immunoglobulin-like domain superfamily / Transferase(Phosphotransferase); domain 1 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-WCJ / Fibroblast growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.79 Å
AuthorsValverde, R. / Foster, L.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Cancer Discov / Year: 2023
Title: RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across FGFR2 Alterations and Resistance Mutations.
Authors: Subbiah, V. / Sahai, V. / Maglic, D. / Bruderek, K. / Toure, B.B. / Zhao, S. / Valverde, R. / O'Hearn, P.J. / Moustakas, D.T. / Schonherr, H. / Gerami-Moayed, N. / Taylor, A.M. / Hudson, B.M. ...Authors: Subbiah, V. / Sahai, V. / Maglic, D. / Bruderek, K. / Toure, B.B. / Zhao, S. / Valverde, R. / O'Hearn, P.J. / Moustakas, D.T. / Schonherr, H. / Gerami-Moayed, N. / Taylor, A.M. / Hudson, B.M. / Houde, D.J. / Pal, D. / Foster, L. / Gunaydin, H. / Ayaz, P. / Sharon, D.A. / Goyal, L. / Schram, A.M. / Kamath, S. / Sherwin, C.A. / Schmidt-Kittler, O. / Jen, K.Y. / Ricard, F. / Wolf, B.B. / Shaw, D.E. / Bergstrom, D.A. / Watters, J. / Casaletto, J.B.
History
DepositionMay 10, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 7, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2023Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Sep 13, 2023Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 2.0Sep 20, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / chem_comp_atom / chem_comp_bond / entity / pdbx_entity_nonpoly
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.label_atom_id / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.name / _entity.formula_weight / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 3.0Oct 18, 2023Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Refinement description
Category: atom_site / pdbx_validate_close_contact ...atom_site / pdbx_validate_close_contact / pdbx_validate_torsion / refine / refine_ls_restr / refine_ls_restr_ncs / refine_ls_shell / software / struct_conn / struct_ncs_dom / struct_ncs_dom_lim / struct_ncs_oper
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.label_atom_id / _refine.B_iso_mean / _refine.ls_R_factor_R_free / _refine.ls_R_factor_R_work / _refine.ls_R_factor_obs / _refine.overall_SU_ML / _refine.pdbx_overall_phase_error / _refine_ls_restr.dev_ideal / _refine_ls_shell.R_factor_R_free / _refine_ls_shell.R_factor_R_work
Description: Ligand geometry
Details: Hi Team, Thank you for letting me address the ligand geometry. I refined the model again, using restrains that would keep the C38 and SG within 1.8 A. Previously that flag was not turned on ...Details: Hi Team, Thank you for letting me address the ligand geometry. I refined the model again, using restrains that would keep the C38 and SG within 1.8 A. Previously that flag was not turned on during refinement. I believe the new model fully reflects the covalent adduct formed by the ligand, which has been validated in solution and is supported by the electron density, up to where the diffraction quality and resolution permits.
Provider: author / Type: Coordinate replacement
Revision 3.1Oct 25, 2023Group: Refinement description / Category: pdbx_initial_refinement_model / Item: _pdbx_initial_refinement_model.details
Revision 3.2Nov 13, 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

Downloads & links

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,5934
Polymers72,5702
Non-polymers1,0232
Water00
1
A: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7962
Polymers36,2851
Non-polymers5121
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7962
Polymers36,2851
Non-polymers5121
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)62.510, 91.340, 129.620
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 Fibroblast growth factor receptor 2 / FGFR-2 / K-sam / KGFR / Keratinocyte growth factor receptor


Mass: 36284.793 Da / Num. of mol.: 2 / Fragment: kinase domain (UNP residues 458-769)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR2, BEK, KGFR, KSAM / Production host: Escherichia coli (E. coli)
References: UniProt: P21802, receptor protein-tyrosine kinase
#2: Chemical ChemComp-WCJ / N-{4-[(5P)-4-amino-5-{3-fluoro-4-[(4-methylpyrimidin-2-yl)oxy]phenyl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl}-2-methylpropanamide


Mass: 511.550 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H26FN7O2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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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: 2.55 Å3/Da / Density % sol: 51.76 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 0.1 M Tris, pH 8, 18-20% w/v PEG8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.000032 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 1, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.000032 Å / Relative weight: 1
ReflectionResolution: 3.787→56.305 Å / Num. obs: 7810 / % possible obs: 99.83 % / Redundancy: 9.56 % / Biso Wilson estimate: 104.87 Å2 / CC1/2: 0.982 / Rmerge(I) obs: 0.123 / Net I/σ(I): 4.3
Reflection shellResolution: 3.787→3.852 Å / Rmerge(I) obs: 1.742 / Num. unique obs: 383 / CC1/2: 0.615 / % possible all: 99.7

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
autoPROCdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3RI1

3ri1


Resolution: 3.79→56.3 Å / SU ML: 0.3744 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 35.5572
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.3106 389 5 %
Rwork0.307 7391 -
obs0.3073 7780 99.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 128.96 Å2
Refinement stepCycle: LAST / Resolution: 3.79→56.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4372 0 76 0 4448
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00594548
X-RAY DIFFRACTIONf_angle_d0.7336152
X-RAY DIFFRACTIONf_chiral_restr0.0427669
X-RAY DIFFRACTIONf_plane_restr0.0069780
X-RAY DIFFRACTIONf_dihedral_angle_d8.129599
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.79-4.340.34181200.34672404X-RAY DIFFRACTION99.68
4.34-5.460.30311330.31952439X-RAY DIFFRACTION99.81
5.47-56.30.30041360.28282548X-RAY DIFFRACTION99.67

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