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- PDB-4aoj: Human TrkA in complex with the inhibitor AZ-23 -

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Basic information

Entry
Database: PDB / ID: 4aoj
TitleHuman TrkA in complex with the inhibitor AZ-23
ComponentsHIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR
KeywordsTRANSFERASE / INHIBITOR
Function / homology
Function and homology information


behavioral response to formalin induced pain / neurotrophin p75 receptor binding / olfactory nerve development / response to hydrostatic pressure / TRKA activation by NGF / PLC-gamma1 signalling / programmed cell death involved in cell development / Signalling to STAT3 / neurotrophin receptor activity / mechanoreceptor differentiation ...behavioral response to formalin induced pain / neurotrophin p75 receptor binding / olfactory nerve development / response to hydrostatic pressure / TRKA activation by NGF / PLC-gamma1 signalling / programmed cell death involved in cell development / Signalling to STAT3 / neurotrophin receptor activity / mechanoreceptor differentiation / nerve growth factor receptor activity / neurotrophin binding / Sertoli cell development / axonogenesis involved in innervation / GPI-linked ephrin receptor activity / nerve growth factor signaling pathway / Retrograde neurotrophin signalling / nerve growth factor binding / NGF-independant TRKA activation / sympathetic nervous system development / 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 / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / detection of temperature stimulus involved in sensory perception of pain / neurotrophin TRK receptor signaling pathway / response to axon injury / neuron development / Signalling to RAS / 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 synaptic transmission, glutamatergic / response to nutrient levels / B cell differentiation / cellular response to nerve growth factor stimulus / positive regulation of GTPase activity / axon guidance / receptor protein-tyrosine kinase / kinase binding / positive regulation of neuron projection development / cellular response to nicotine / circadian rhythm / peptidyl-tyrosine phosphorylation / recycling endosome membrane / positive regulation of angiogenesis / neuron projection development / late endosome / late endosome membrane / positive regulation of NF-kappaB transcription factor activity / early endosome membrane / protein tyrosine kinase activity / neuron apoptotic process / negative regulation of neuron apoptotic process / protein autophosphorylation / learning or memory / positive regulation of ERK1 and ERK2 cascade / early endosome / receptor complex / endosome membrane / response to xenobiotic stimulus / positive regulation of protein phosphorylation / negative regulation of cell population proliferation / axon / protein phosphorylation / neuronal cell body / dendrite / negative regulation of apoptotic process / cell surface / protein homodimerization activity / protein-containing complex / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / 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-V4Z / High affinity nerve growth factor receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.75 Å
AuthorsWang, T. / Lamb, M.L. / Block, M.H. / Davies, A.M. / Han, Y. / Hoffmann, E. / Ioannidis, S. / Josey, J.A. / Liu, Z. / Lyne, P.D. ...Wang, T. / Lamb, M.L. / Block, M.H. / Davies, A.M. / Han, Y. / Hoffmann, E. / Ioannidis, S. / Josey, J.A. / Liu, Z. / Lyne, P.D. / MacIntyre, T. / Mohr, P.J. / Omer, C.A. / Sjogren, T. / Thress, K. / Wang, B. / Wang, H. / Yu, D. / Zhang, H.
CitationJournal: Acs Med.Chem.Lett. / Year: 2012
Title: Discovery of Disubstituted Imidazo[4,5-B]Pyridines and Purines as Potent Trka Inhibitors
Authors: Wang, T. / Lamb, M.L. / Block, M.H. / Davies, A.M. / Han, Y. / Hoffmann, E. / Ioannidis, S. / Josey, J.A. / Liu, Z. / Lyne, P.D. / Macintyre, T. / Mohr, P.J. / Omer, C.A. / Sjogren, T. / ...Authors: Wang, T. / Lamb, M.L. / Block, M.H. / Davies, A.M. / Han, Y. / Hoffmann, E. / Ioannidis, S. / Josey, J.A. / Liu, Z. / Lyne, P.D. / Macintyre, T. / Mohr, P.J. / Omer, C.A. / Sjogren, T. / Thress, K. / Wang, B. / Wang, H. / Yu, D. / Zhang, H.
History
DepositionMar 28, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 15, 2012Provider: repository / Type: Initial release
Revision 1.1Oct 31, 2012Group: Database references
Revision 1.2Jun 18, 2014Group: Database references
Revision 1.3May 8, 2019Group: Data collection / Experimental preparation / Other
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval
Revision 1.4Dec 20, 2023Group: 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 / pdbx_struct_conn_angle / 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 / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry / _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: HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR
B: HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR
C: HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,26312
Polymers110,6953
Non-polymers1,5689
Water1,49583
1
A: HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR
B: HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR
C: HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR
hetero molecules

A: HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR
B: HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR
C: HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR
hetero molecules

A: HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR
B: HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR
C: HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR
hetero molecules

A: HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR
B: HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR
C: HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)449,05248
Polymers442,78112
Non-polymers6,27236
Water21612
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_665-x+1,-y+1,z1
crystal symmetry operation3_655-x+1,y,-z1
crystal symmetry operation4_565x,-y+1,-z1
Buried area26280 Å2
ΔGint-1062.1 kcal/mol
Surface area136750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)130.727, 158.419, 152.577
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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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 / TRKA


Mass: 36898.379 Da / Num. of mol.: 3 / Fragment: KINASE DOMAIN, RESIDUES 473-796
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFASTBAC HTB / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P04629, receptor protein-tyrosine kinase
#2: Chemical ChemComp-V4Z / 5-chloranyl-N2-[(1S)-1-(5-fluoranylpyridin-2-yl)ethyl]-N4-(3-propan-2-yloxy-1H-pyrazol-5-yl)pyrimidine-2,4-diamine


Mass: 391.830 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C17H19ClFN7O
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 83 / 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: 3.56 Å3/Da / Density % sol: 65 % / Description: NONE
Crystal growMethod: vapor diffusion, hanging drop / pH: 8
Details: HANGING DROP METHOD. 1 UL TRKA AT 10 MG/ML IN 10 MG/ML IN 20 MM TRIS PH 8.5, 0.1% CHAPS, 1MM TCEP, 8.7% GLYCEROL MIXED WITH 1 UL MOTHER LIQUOR CONTAINING 35% W/V GLYCEROL, 140 MM NA/K ...Details: HANGING DROP METHOD. 1 UL TRKA AT 10 MG/ML IN 10 MG/ML IN 20 MM TRIS PH 8.5, 0.1% CHAPS, 1MM TCEP, 8.7% GLYCEROL MIXED WITH 1 UL MOTHER LIQUOR CONTAINING 35% W/V GLYCEROL, 140 MM NA/K TARTRATE, 100 MM HEPES PH 8.0 SUPPLEMENTED WITH 40 MM ZINC CHLORIDE.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.94
DetectorType: ADSC CCD / Detector: CCD / Date: Nov 2, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.94 Å / Relative weight: 1
ReflectionResolution: 2.75→42.06 Å / Num. obs: 41385 / % possible obs: 99.9 % / Observed criterion σ(I): 2 / Redundancy: 3.6 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 13
Reflection shellResolution: 2.75→2.82 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.38 / Mean I/σ(I) obs: 3 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1R0P

1r0p


Resolution: 2.75→40 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.907 / SU B: 8.435 / SU ML: 0.175 / Cross valid method: THROUGHOUT / ESU R: 0.455 / ESU R Free: 0.284 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.24217 1980 5 %RANDOM
Rwork0.21958 ---
obs0.2207 37674 95.62 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 55.732 Å2
Baniso -1Baniso -2Baniso -3
1--2.59 Å20 Å20 Å2
2--0.31 Å20 Å2
3---2.27 Å2
Refinement stepCycle: LAST / Resolution: 2.75→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6234 0 87 83 6404
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0226486
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.5741.9638771
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2985769
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.07522.458301
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.011151087
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.9611560
X-RAY DIFFRACTIONr_chiral_restr0.1340.2933
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0215053
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.4621.53870
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.06426206
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it6.05632616
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it9.0144.52564
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.75→2.821 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.388 135 -
Rwork0.281 2570 -
obs--89.39 %

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