[English] 日本語
Yorodumi
- PDB-4yps: (R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Clas... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 4yps
Title(R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Class of Potent and Selective Pan-TRK Inhibitors
ComponentsHigh affinity nerve growth factor receptor
KeywordsTransfease/Transferase Inhibitor / TrkA / Kinase / Oncology / Inhibitor complex. / Transfease-Transferase Inhibitor complex
Function / homology
Function and homology information


neurotrophin p75 receptor binding / behavioral response to formalin induced pain / olfactory nerve development / response to hydrostatic pressure / TRKA activation by NGF / PLC-gamma1 signalling / Signalling to STAT3 / neurotrophin receptor activity / programmed cell death involved in cell development / mechanoreceptor differentiation ...neurotrophin p75 receptor binding / behavioral response to formalin induced pain / olfactory nerve development / response to hydrostatic pressure / TRKA activation by NGF / PLC-gamma1 signalling / Signalling to STAT3 / neurotrophin receptor activity / programmed cell death involved in cell development / mechanoreceptor differentiation / nerve growth factor receptor activity / neurotrophin binding / nerve growth factor signaling pathway / axonogenesis involved in innervation / Sertoli cell development / Retrograde neurotrophin signalling / nerve growth factor binding / sympathetic nervous system development / NGF-independant TRKA activation / Signalling to p38 via RIT and RIN / ARMS-mediated activation / positive regulation of Ras protein signal transduction / positive regulation of programmed cell death / positive regulation of synapse assembly / PI3K/AKT activation / Frs2-mediated activation / neurotrophin TRK receptor signaling pathway / detection of temperature stimulus involved in sensory perception of pain / Signalling to RAS / response to axon injury / neuron development / detection of mechanical stimulus involved in sensory perception of pain / response to electrical stimulus / peptidyl-tyrosine autophosphorylation / transmembrane receptor protein tyrosine kinase activity / positive regulation of GTPase activity / B cell differentiation / positive regulation of synaptic transmission, glutamatergic / axon guidance / cell surface receptor protein tyrosine kinase signaling pathway / cellular response to nerve growth factor stimulus / response to nutrient levels / 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 / peptidyl-tyrosine phosphorylation / positive regulation of neuron projection development / cellular response to nicotine / kinase binding / recycling endosome membrane / circadian rhythm / positive regulation of angiogenesis / neuron projection development / positive regulation of NF-kappaB transcription factor activity / late endosome membrane / late endosome / protein autophosphorylation / protein tyrosine kinase activity / early endosome membrane / neuron apoptotic process / spermatogenesis / negative regulation of neuron apoptotic process / learning or memory / early endosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of ERK1 and ERK2 cascade / endosome membrane / protein phosphorylation / response to xenobiotic stimulus / axon / negative regulation of cell population proliferation / neuronal cell body / dendrite / negative regulation of apoptotic process / cell surface / protein homodimerization activity / protein-containing complex / mitochondrion / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
High affinity nerve growth factor receptor NTRK1 / Tyrosine kinase receptor A, transmembrane domain / Tyrosine kinase receptor A trans-membrane domain / Growth factor receptor NTRK / Growth factor receptor NTRK, leucine rich repeat C-terminal / Leucine rich repeat C-terminal motif / 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. ...High affinity nerve growth factor receptor NTRK1 / Tyrosine kinase receptor A, transmembrane domain / Tyrosine kinase receptor A trans-membrane domain / Growth factor receptor NTRK / Growth factor receptor NTRK, leucine rich repeat C-terminal / Leucine rich repeat C-terminal motif / 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. / Leucine rich repeat / : / Leucine-rich repeat / Leucine-rich repeat domain 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 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-4F6 / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1012 Å
AuthorsKreusch, A. / Rucker, P. / Molteni, V. / Loren, J.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: (R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors.
Authors: Choi, H.S. / Rucker, P.V. / Wang, Z. / Fan, Y. / Albaugh, P. / Chopiuk, G. / Gessier, F. / Sun, F. / Adrian, F. / Liu, G. / Hood, T. / Li, N. / Jia, Y. / Che, J. / McCormack, S. / Li, A. / ...Authors: Choi, H.S. / Rucker, P.V. / Wang, Z. / Fan, Y. / Albaugh, P. / Chopiuk, G. / Gessier, F. / Sun, F. / Adrian, F. / Liu, G. / Hood, T. / Li, N. / Jia, Y. / Che, J. / McCormack, S. / Li, A. / Li, J. / Steffy, A. / Culazzo, A. / Tompkins, C. / Phung, V. / Kreusch, A. / Lu, M. / Hu, B. / Chaudhary, A. / Prashad, M. / Tuntland, T. / Liu, B. / Harris, J. / Seidel, H.M. / Loren, J. / Molteni, V.
History
DepositionMar 13, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 3, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity_src_gen / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: High affinity nerve growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0456
Polymers34,2621
Non-polymers7845
Water90150
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)106.481, 106.481, 204.511
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number155
Space group name H-MH32

-
Components

#1: Protein High affinity nerve growth factor receptor / Neurotrophic tyrosine kinase receptor type 1 / TRK1-transforming tyrosine kinase protein / ...Neurotrophic tyrosine kinase receptor type 1 / TRK1-transforming tyrosine kinase protein / Tropomyosin-related kinase A / Tyrosine kinase receptor / Tyrosine kinase receptor A / Trk-A / gp140trk / p140-TrkA


Mass: 34261.613 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NTRK1, MTC, TRK, TRKA / Plasmid: pFastBac1-HM / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P04629, receptor protein-tyrosine kinase
#2: Chemical ChemComp-4F6 / 4-{6-[(3R)-3-(3-fluorophenyl)morpholin-4-yl]imidazo[1,2-b]pyridazin-3-yl}benzonitrile


Mass: 399.420 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H18FN5O
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 50 / Source method: isolated from a natural source / Formula: H2O

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 3.26 Å3/Da / Density % sol: 62.23 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5 / Details: 0.8M (NH4)2SO4, 0.1M Citrate pH 5.0

-
Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9765 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 29, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 2.1→34.36 Å / Num. obs: 26115 / % possible obs: 99.7 % / Redundancy: 5.4 % / Biso Wilson estimate: 48 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 7.8
Reflection shellResolution: 2.1→2.14 Å / % possible all: 94.7

-
Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.9_1692)refinement
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4YNE

4yne


Resolution: 2.1012→34.36 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 0.27 / Phase error: 29.64 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2574 1318 5.05 %Random Selection
Rwork0.2008 ---
obs0.2035 26115 99.24 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 67 Å2
Refinement stepCycle: LAST / Resolution: 2.1012→34.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2155 0 50 50 2255
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092255
X-RAY DIFFRACTIONf_angle_d1.1763064
X-RAY DIFFRACTIONf_dihedral_angle_d15.136790
X-RAY DIFFRACTIONf_chiral_restr0.045333
X-RAY DIFFRACTIONf_plane_restr0.005388
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1012-2.18530.34421270.31922594X-RAY DIFFRACTION94
2.1853-2.28480.35211490.2992712X-RAY DIFFRACTION100
2.2848-2.40520.35271320.27842767X-RAY DIFFRACTION100
2.4052-2.55590.28311590.252740X-RAY DIFFRACTION100
2.5559-2.75310.29031640.24432724X-RAY DIFFRACTION100
2.7531-3.030.27791460.21882763X-RAY DIFFRACTION100
3.03-3.46810.25931640.2012755X-RAY DIFFRACTION100
3.4681-4.36810.21851330.172830X-RAY DIFFRACTION100
4.3681-34.360.23661440.17782912X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -25.9658 Å / Origin y: -43.7469 Å / Origin z: -19.6069 Å
111213212223313233
T0.3975 Å20.0801 Å20.0464 Å2-0.3531 Å2-0.0104 Å2--0.2856 Å2
L3.88 °20.9273 °20.4927 °2-2.2542 °2-0.1463 °2--4.3948 °2
S-0.0951 Å °-0.1248 Å °0.1251 Å °-0.0885 Å °-0.0841 Å °0.0084 Å °-0.3879 Å °0.173 Å °0.1459 Å °
Refinement TLS groupSelection details: all

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more