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Basic information

Entry
Database: PDB / ID: 7cc2
TitleStrategic design of catalytic lysine-targeting reversible covalent BCR-ABL Inhibitors
ComponentsTyrosine-protein kinase ABL1
KeywordsTRANSFERASE / Tyrosine kinase Covalent inhibitor chronic myelogenous leukemia
Function / homology
Function and homology information


: / positive regulation of actin filament binding / negative regulation of ubiquitin-protein transferase activity / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / DN4 thymocyte differentiation / response to epinephrine / activation of protein kinase C activity / phospholipase C-inhibiting G protein-coupled receptor signaling pathway / podocyte apoptotic process ...: / positive regulation of actin filament binding / negative regulation of ubiquitin-protein transferase activity / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / DN4 thymocyte differentiation / response to epinephrine / activation of protein kinase C activity / phospholipase C-inhibiting G protein-coupled receptor signaling pathway / podocyte apoptotic process / delta-catenin binding / Role of ABL in ROBO-SLIT signaling / transitional one stage B cell differentiation / regulation of postsynaptic specialization assembly / regulation of modification of synaptic structure / nicotinate-nucleotide adenylyltransferase activity / cerebellum morphogenesis / neuroepithelial cell differentiation / B cell proliferation involved in immune response / positive regulation of extracellular matrix organization / positive regulation of Wnt signaling pathway, planar cell polarity pathway / microspike assembly / B-1 B cell homeostasis / neuropilin signaling pathway / neuropilin binding / bubble DNA binding / mitochondrial depolarization / regulation of cell motility / positive regulation of establishment of T cell polarity / activated T cell proliferation / cellular response to dopamine / positive regulation of blood vessel branching / proline-rich region binding / negative regulation of mitotic cell cycle / regulation of Cdc42 protein signal transduction / mitogen-activated protein kinase binding / regulation of hematopoietic stem cell differentiation / syntaxin binding / alpha-beta T cell differentiation / positive regulation of dendrite development / positive regulation of cell migration involved in sprouting angiogenesis / peptidyl-tyrosine autophosphorylation / regulation of axon extension / regulation of T cell differentiation / positive regulation of peptidyl-tyrosine phosphorylation / negative regulation of cell-cell adhesion / HDR through Single Strand Annealing (SSA) / neuromuscular process controlling balance / Myogenesis / positive regulation of osteoblast proliferation / platelet-derived growth factor receptor-beta signaling pathway / positive regulation of vasoconstriction / RUNX2 regulates osteoblast differentiation / Fc-gamma receptor signaling pathway involved in phagocytosis / vascular endothelial cell response to oscillatory fluid shear stress / regulation of endocytosis / Bergmann glial cell differentiation / regulation of microtubule polymerization / myoblast proliferation / negative regulation of long-term synaptic potentiation / associative learning / negative regulation of cellular senescence / actin monomer binding / signal transduction in response to DNA damage / positive regulation of focal adhesion assembly / canonical NF-kappaB signal transduction / negative regulation of BMP signaling pathway / RHO GTPases Activate WASPs and WAVEs / cardiac muscle cell proliferation / ephrin receptor signaling pathway / positive regulation of T cell migration / endothelial cell migration / BMP signaling pathway / negative regulation of double-strand break repair via homologous recombination / cellular response to transforming growth factor beta stimulus / negative regulation of endothelial cell apoptotic process / mismatch repair / regulation of cell adhesion / ephrin receptor binding / four-way junction DNA binding / spleen development / positive regulation of stress fiber assembly / ruffle / ERK1 and ERK2 cascade / actin filament polymerization / phosphotyrosine residue binding / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of interleukin-2 production / positive regulation of endothelial cell migration / SH2 domain binding / substrate adhesion-dependent cell spreading / positive regulation of mitotic cell cycle / protein kinase C binding / response to endoplasmic reticulum stress / peptidyl-tyrosine phosphorylation / positive regulation of release of sequestered calcium ion into cytosol / thymus development / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / integrin-mediated signaling pathway / post-embryonic development
Similarity search - Function
F-actin binding / F-actin binding / F-actin binding domain (FABD) / Tyrosine-protein kinase ABL, SH2 domain / : / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain ...F-actin binding / F-actin binding / F-actin binding domain (FABD) / Tyrosine-protein kinase ABL, SH2 domain / : / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / 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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-FVC / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.723 Å
AuthorsAnantharajan, J. / Baburajendran, N.
Funding support Singapore, 1items
OrganizationGrant numberCountry
National Medical Research Council Singapore
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2021
Title: Strategic Design of Catalytic Lysine-Targeting Reversible Covalent BCR-ABL Inhibitors*.
Authors: Quach, D. / Tang, G. / Anantharajan, J. / Baburajendran, N. / Poulsen, A. / Wee, J.L.K. / Retna, P. / Li, R. / Liu, B. / Tee, D.H.Y. / Kwek, P.Z. / Joy, J.K. / Yang, W.Q. / Zhang, C.J. / ...Authors: Quach, D. / Tang, G. / Anantharajan, J. / Baburajendran, N. / Poulsen, A. / Wee, J.L.K. / Retna, P. / Li, R. / Liu, B. / Tee, D.H.Y. / Kwek, P.Z. / Joy, J.K. / Yang, W.Q. / Zhang, C.J. / Foo, K. / Keller, T.H. / Yao, S.Q.
History
DepositionJun 16, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 9, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 28, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Nov 29, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.3Oct 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

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase ABL1
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,5904
Polymers71,7902
Non-polymers8002
Water81145
1
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,2952
Polymers35,8951
Non-polymers4001
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,2952
Polymers35,8951
Non-polymers4001
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)116.489, 127.939, 56.760
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 233 through 237 or (resid 238...
21(chain B and (resid 233 through 248 or resid 255...

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ASPASPMETMET(chain A and (resid 233 through 237 or (resid 238...AA233 - 23733 - 37
12GLUGLUGLUGLU(chain A and (resid 233 through 237 or (resid 238...AA23838
13ASPASPSERSER(chain A and (resid 233 through 237 or (resid 238...AA233 - 50133 - 301
14ASPASPSERSER(chain A and (resid 233 through 237 or (resid 238...AA233 - 50133 - 301
15ASPASPSERSER(chain A and (resid 233 through 237 or (resid 238...AA233 - 50133 - 301
16ASPASPSERSER(chain A and (resid 233 through 237 or (resid 238...AA233 - 50133 - 301
21ASPASPLEULEU(chain B and (resid 233 through 248 or resid 255...BB233 - 24833 - 48
22GLUGLUTHRTHR(chain B and (resid 233 through 248 or resid 255...BB255 - 27755 - 77
23METMETPHEPHE(chain B and (resid 233 through 248 or resid 255...BB278 - 28378 - 83
24TYRTYRSERSER(chain B and (resid 233 through 248 or resid 255...BB232 - 50132 - 301
25TYRTYRSERSER(chain B and (resid 233 through 248 or resid 255...BB232 - 50132 - 301
26TYRTYRSERSER(chain B and (resid 233 through 248 or resid 255...BB232 - 50132 - 301
27TYRTYRSERSER(chain B and (resid 233 through 248 or resid 255...BB232 - 50132 - 301
28TYRTYRSERSER(chain B and (resid 233 through 248 or resid 255...BB232 - 50132 - 301

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Components

#1: Protein Tyrosine-protein kinase ABL1 / Abelson murine leukemia viral oncogene homolog 1 / Abelson tyrosine-protein kinase 1 / Proto- ...Abelson murine leukemia viral oncogene homolog 1 / Abelson tyrosine-protein kinase 1 / Proto-oncogene c-Abl / p150


Mass: 35894.848 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABL1, ABL, JTK7 / Production host: Escherichia coli (E. coli)
References: UniProt: P00519, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-FVC / [4-[5-[5-(dimethylcarbamoyl)pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-2-methyl-phenyl]boronic acid


Mass: 400.238 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H21BN4O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 45 / Source method: isolated from a natural source / Formula: H2O
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: 2.93 Å3/Da / Density % sol: 57.98 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop
Details: 7 % w/v Polyethylene glycol 8000, 100 mM MES pH 6.5, 20 % v/v Ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.95374 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 28, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95374 Å / Relative weight: 1
ReflectionResolution: 2.72→47.395 Å / Num. obs: 23393 / % possible obs: 99.5 % / Redundancy: 6.7 % / Biso Wilson estimate: 43.73 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.144 / Rpim(I) all: 0.06 / Rrim(I) all: 0.157 / Net I/σ(I): 8.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.72-2.856.80.75330000.7850.3070.81597.6
9.02-47.3956.20.0417240.9990.0170.04498.5

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
Aimless0.7.2data scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2QOH

2qoh


Resolution: 2.723→47.39 Å / SU ML: 0.33 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 22.53 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2418 2000 8.57 %
Rwork0.1922 21343 -
obs0.1964 23343 99.61 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 129.3 Å2 / Biso mean: 46.1251 Å2 / Biso min: 13.4 Å2
Refinement stepCycle: final / Resolution: 2.723→47.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4303 0 0 45 4348
Biso mean---34.99 -
Num. residues----529
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034418
X-RAY DIFFRACTIONf_angle_d0.6765985
X-RAY DIFFRACTIONf_chiral_restr0.045643
X-RAY DIFFRACTIONf_plane_restr0.003746
X-RAY DIFFRACTIONf_dihedral_angle_d5.4942596
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2398X-RAY DIFFRACTION8.779TORSIONAL
12B2398X-RAY DIFFRACTION8.779TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.723-2.7910.35551380.2615147399
2.791-2.86640.31211400.229148899
2.8664-2.95070.29861410.21521515100
2.9507-3.0460.28431400.22111493100
3.046-3.15480.24961420.20151512100
3.1548-3.28110.31521400.20511502100
3.2811-3.43040.23781420.20061507100
3.4304-3.61120.211420.18171517100
3.6112-3.83730.23431420.1861514100
3.8373-4.13350.22891430.17441532100
4.1335-4.54910.1861440.1671528100
4.5491-5.20670.19861450.16841563100
5.2067-6.55710.23371470.20471558100
6.5571-47.390.26591540.1943164199

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