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- PDB-2zm3: Complex Structure of Insulin-like Growth Factor Receptor and Isoq... -

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Basic information

Entry
Database: PDB / ID: 2zm3
TitleComplex Structure of Insulin-like Growth Factor Receptor and Isoquinolinedione Inhibitor
ComponentsInsulin-like growth factor 1 receptor
KeywordsTRANSFERASE / IGFR / protein-inhibitor complex / tyrosine kinase / ATP-binding / Cleavage on pair of basic residues / Disease mutation / Glycoprotein / Membrane / Nucleotide-binding / Phosphoprotein / Polymorphism / Receptor / Transmembrane / Tyrosine-protein kinase
Function / homology
Function and homology information


protein kinase complex / insulin-like growth factor receptor activity / insulin-like growth factor binding / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / protein transporter activity / IRS-related events triggered by IGF1R / transcytosis / insulin receptor complex / insulin-like growth factor I binding / positive regulation of protein-containing complex disassembly ...protein kinase complex / insulin-like growth factor receptor activity / insulin-like growth factor binding / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / protein transporter activity / IRS-related events triggered by IGF1R / transcytosis / insulin receptor complex / insulin-like growth factor I binding / positive regulation of protein-containing complex disassembly / insulin receptor activity / alphav-beta3 integrin-IGF-1-IGF1R complex / regulation of JNK cascade / dendritic spine maintenance / peptidyl-tyrosine autophosphorylation / insulin binding / amyloid-beta clearance / Respiratory syncytial virus (RSV) attachment and entry / insulin receptor substrate binding / SHC-related events triggered by IGF1R / phosphatidylinositol 3-kinase binding / negative regulation of MAPK cascade / insulin-like growth factor receptor signaling pathway / insulin receptor binding / cellular response to glucose stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor protein-tyrosine kinase / cellular response to amyloid-beta / insulin receptor signaling pathway / positive regulation of cold-induced thermogenesis / protein autophosphorylation / protein tyrosine kinase activity / Extra-nuclear estrogen signaling / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of MAPK cascade / immune response / cilium / positive regulation of cell migration / axon / intracellular membrane-bounded organelle / positive regulation of cell population proliferation / negative regulation of apoptotic process / nucleolus / signal transduction / ATP binding / identical protein binding / membrane / plasma membrane
Similarity search - Function
Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats ...Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / Growth factor receptor cysteine-rich domain superfamily / : / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III 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. / 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-575 / Insulin-like growth factor 1 receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsXu, W. / Mayer, S.C. / Boschelli, F. / Johnson, M. / Dwyer, B.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: Lead identification to generate isoquinolinedione inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment
Authors: Mayer, S.C. / Banker, A.L. / Boschelli, F. / Di, L. / Johnson, M. / Kenny, C.H. / Krishnamurthy, G. / Kutterer, K. / Moy, F. / Petusky, S. / Ravi, M. / Tkach, D. / Tsou, H.R. / Xu, W.
History
DepositionApr 10, 2008Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 10, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / 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_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.4Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Insulin-like growth factor 1 receptor
B: Insulin-like growth factor 1 receptor
C: Insulin-like growth factor 1 receptor
D: Insulin-like growth factor 1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)143,0748
Polymers141,3694
Non-polymers1,7054
Water8,233457
1
A: Insulin-like growth factor 1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7682
Polymers35,3421
Non-polymers4261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Insulin-like growth factor 1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7682
Polymers35,3421
Non-polymers4261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Insulin-like growth factor 1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7682
Polymers35,3421
Non-polymers4261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Insulin-like growth factor 1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7682
Polymers35,3421
Non-polymers4261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
A: Insulin-like growth factor 1 receptor
hetero molecules

A: Insulin-like growth factor 1 receptor
hetero molecules

D: Insulin-like growth factor 1 receptor
hetero molecules

D: Insulin-like growth factor 1 receptor
hetero molecules

B: Insulin-like growth factor 1 receptor
C: Insulin-like growth factor 1 receptor
hetero molecules

B: Insulin-like growth factor 1 receptor
C: Insulin-like growth factor 1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)286,14816
Polymers282,7378
Non-polymers3,4108
Water1448
TypeNameSymmetry operationNumber
crystal symmetry operation3_454x-1/2,y+1/2,z-11
crystal symmetry operation4_556-x+1/2,y+1/2,-z+11
crystal symmetry operation1_554x,y,z-11
crystal symmetry operation2_556-x,y,-z+11
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area18530 Å2
ΔGint-91.1 kcal/mol
Surface area102410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)137.725, 135.962, 86.380
Angle α, β, γ (deg.)90.00, 114.27, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-376-

HOH

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Components

#1: Protein
Insulin-like growth factor 1 receptor / Insulin-like growth factor I receptor / IGF-I receptor / CD221 antigen


Mass: 35342.145 Da / Num. of mol.: 4 / Fragment: UNP residues 981-1286, IGF-1R Kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IGF1R
References: UniProt: P08069, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-575 / (4Z)-6-bromo-4-({[4-(pyrrolidin-1-ylmethyl)phenyl]amino}methylidene)isoquinoline-1,3(2H,4H)-dione


Mass: 426.306 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H20BrN3O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 457 / Source method: isolated from a natural source / Formula: H2O
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: 2.61 Å3/Da / Density % sol: 52.83 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 0.1M Tris-HCl, pH8, 2M NaCl, 13-16% PEG6K, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 143 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jan 28, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.27→50 Å / Num. obs: 60396 / % possible obs: 90.8 % / Rmerge(I) obs: 0.096
Reflection shellResolution: 2.45→2.56 Å / Rmerge(I) obs: 0.462 / Mean I/σ(I) obs: 1.8 / Num. unique all: 5939 / Rsym value: 0.462 / % possible all: 75.8

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Processing

Software
NameVersionClassification
PHENIXrefinement
ADSCQuantumdata collection
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1JQH

1jqh


Resolution: 2.5→46.37 Å / Isotropic thermal model: isotropic / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2572 2480 5.05 %random
Rwork0.2009 ---
all0.2037 50128 --
obs0.2037 49126 98 %-
Displacement parametersBiso mean: 32.81 Å2
Refinement stepCycle: LAST / Resolution: 2.5→46.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9592 0 108 457 10157
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONf_bond_d0.003
X-RAY DIFFRACTIONf_angle_d0.829

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