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- PDB-2v7a: Crystal structure of the T315I Abl mutant in complex with the inh... -

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Basic information

Entry
Database: PDB / ID: 2v7a
TitleCrystal structure of the T315I Abl mutant in complex with the inhibitor PHA-739358
ComponentsPROTO-ONCOGENE TYROSINE-PROTEIN KINASE ABL1
KeywordsTRANSFERASE / KINASE / NUCLEUS / MYRISTATE / CYTOPLASM / MANGANESE / CELL ADHESION / METAL-BINDING / PROTO-ONCOGENE / TYROSINE-PROTEIN KINASE / CHROMOSOMAL REARRANGEMENT / LIPOPROTEIN / POLYMORPHISM / CYTOSKELETON / MAGNESIUM / SH2 DOMAIN / SH3 DOMAIN / ATP-BINDING / NUCLEOTIDE-BINDING / ALTERNATIVE SPLICING / PHOSPHORYLATION / KINASE INHIBITOR / T315I ABL MUTANT
Function / homology
Function and homology information


negative regulation of phospholipase C activity / positive regulation of actin filament binding / positive regulation of oxidoreductase activity / transitional one stage B cell differentiation / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / podocyte apoptotic process / DN4 thymocyte differentiation / Role of ABL in ROBO-SLIT signaling / response to epinephrine ...negative regulation of phospholipase C activity / positive regulation of actin filament binding / positive regulation of oxidoreductase activity / transitional one stage B cell differentiation / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / podocyte apoptotic process / DN4 thymocyte differentiation / Role of ABL in ROBO-SLIT signaling / response to epinephrine / activation of protein kinase C activity / nicotinate-nucleotide adenylyltransferase activity / regulation of modification of synaptic structure / positive regulation of extracellular matrix organization / positive regulation of microtubule binding / delta-catenin binding / B cell proliferation involved in immune response / neuroepithelial cell differentiation / microspike assembly / positive regulation of Wnt signaling pathway, planar cell polarity pathway / cerebellum morphogenesis / positive regulation of blood vessel branching / B-1 B cell homeostasis / mitochondrial depolarization / negative regulation of ubiquitin-protein transferase activity / neuropilin signaling pathway / neuropilin binding / bubble DNA binding / negative regulation of protein serine/threonine kinase activity / regulation of Cdc42 protein signal transduction / activated T cell proliferation / cellular response to dopamine / regulation of cell motility / regulation of axon extension / proline-rich region binding / positive regulation of dendrite development / mitogen-activated protein kinase binding / myoblast proliferation / alpha-beta T cell differentiation / regulation of hematopoietic stem cell differentiation / syntaxin binding / cardiac muscle cell proliferation / HDR through Single Strand Annealing (SSA) / regulation of T cell differentiation / negative regulation of double-strand break repair via homologous recombination / positive regulation of cell migration involved in sprouting angiogenesis / Fc-gamma receptor signaling pathway involved in phagocytosis / negative regulation of cell-cell adhesion / Myogenesis / regulation of microtubule polymerization / positive regulation of osteoblast proliferation / RUNX2 regulates osteoblast differentiation / negative regulation of cellular senescence / platelet-derived growth factor receptor-beta signaling pathway / positive regulation of focal adhesion assembly / negative regulation of long-term synaptic potentiation / Bergmann glial cell differentiation / associative learning / neuromuscular process controlling balance / regulation of endocytosis / actin monomer binding / negative regulation of BMP signaling pathway / negative regulation of mitotic cell cycle / mismatch repair / endothelial cell migration / RHO GTPases Activate WASPs and WAVEs / positive regulation of T cell migration / BMP signaling pathway / canonical NF-kappaB signal transduction / negative regulation of endothelial cell apoptotic process / regulation of cell adhesion / positive regulation of substrate adhesion-dependent cell spreading / four-way junction DNA binding / signal transduction in response to DNA damage / peptidyl-tyrosine autophosphorylation / positive regulation of vasoconstriction / spleen development / positive regulation of stress fiber assembly / ruffle / ERK1 and ERK2 cascade / cellular response to transforming growth factor beta stimulus / positive regulation of establishment of T cell polarity / positive regulation of interleukin-2 production / actin filament polymerization / SH2 domain binding / response to endoplasmic reticulum stress / phosphotyrosine residue binding / ephrin receptor binding / positive regulation of mitotic cell cycle / substrate adhesion-dependent cell spreading / post-embryonic development / protein kinase C binding / positive regulation of release of sequestered calcium ion into cytosol / positive regulation of endothelial cell migration / thymus development / regulation of autophagy / neural tube closure / integrin-mediated signaling pathway / establishment of localization in cell / regulation of actin cytoskeleton organization
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 / Src homology 3 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 / Src homology 3 domains / SH2 domain / 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 / 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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / 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-627 / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsModugno, M. / Casale, E. / Soncini, C. / Rosettani, P. / Colombo, R. / Lupi, R. / Rusconi, L. / Fancelli, D. / Carpinelli, P. / Cameron, A.D. ...Modugno, M. / Casale, E. / Soncini, C. / Rosettani, P. / Colombo, R. / Lupi, R. / Rusconi, L. / Fancelli, D. / Carpinelli, P. / Cameron, A.D. / Isacchi, A. / Moll, J.
CitationJournal: Cancer Res. / Year: 2007
Title: Crystal Structure of the T315I Abl Mutant in Complex with the Aurora Kinases Inhibitor Pha-739358.
Authors: Modugno, M. / Casale, E. / Soncini, C. / Rosettani, P. / Colombo, R. / Lupi, R. / Rusconi, L. / Fancelli, D. / Carpinelli, P. / Cameron, A.D. / Isacchi, A. / Moll, J.
History
DepositionJul 27, 2007Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 18, 2007Provider: repository / Type: Initial release
Revision 1.1Jul 29, 2015Group: Non-polymer description / Other / Version format compliance
Revision 1.2Apr 3, 2019Group: Data collection / Derived calculations ...Data collection / Derived calculations / Other / Source and taxonomy
Category: entity_src_gen / pdbx_database_proc ...entity_src_gen / pdbx_database_proc / pdbx_database_status / pdbx_seq_map_depositor_info / struct_conn
Item: _entity_src_gen.pdbx_host_org_cell_line / _pdbx_database_status.recvd_author_approval ..._entity_src_gen.pdbx_host_org_cell_line / _pdbx_database_status.recvd_author_approval / _pdbx_seq_map_depositor_info.one_letter_code_mod / _struct_conn.pdbx_leaving_atom_flag
Revision 1.3Oct 16, 2019Group: Data collection / Other / Category: pdbx_database_status / reflns_shell
Item: _pdbx_database_status.status_code_sf / _reflns_shell.Rmerge_I_obs
Revision 1.4Dec 13, 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 / 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_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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_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: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE ABL1
B: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,2836
Polymers66,2862
Non-polymers9984
Water2,990166
1
A: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6423
Polymers33,1431
Non-polymers4992
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
2
B: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6423
Polymers33,1431
Non-polymers4992
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)159.757, 159.757, 56.931
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number171
Space group name H-MP62

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Components

#1: Protein PROTO-ONCOGENE TYROSINE-PROTEIN KINASE ABL1 / ABELSON MURINE LEUKEMIA VIRAL ONCOGENE HOMOLOG 1 / P150 / C-ABL


Mass: 33142.793 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN, RESIDUES 229-512 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): High Five / Production host: AUTOGRAPHA (butterflies/moths)
References: UniProt: P00519, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-627 / N-[(3E)-5-[(2R)-2-METHOXY-2-PHENYLACETYL]PYRROLO[3,4-C]PYRAZOL-3(5H)-YLIDENE]-4-(4-METHYLPIPERAZIN-1-YL)BENZAMIDE / Danusertib / PHA-739358


Mass: 474.555 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H30N6O3
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 166 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, THR 315 TO ILE ENGINEERED RESIDUE IN CHAIN B, THR 315 TO ILE

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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: 3.2 Å3/Da / Density % sol: 61 % / Description: NONE
Crystal growDetails: 20% PEG 4000 ,1M HEPES PH 7.0, 0.1 M MGCL2,

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.93
DetectorType: ADSC CCD / Detector: CCD / Date: Dec 1, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.93 Å / Relative weight: 1
ReflectionResolution: 2.5→30 Å / Num. obs: 29049 / % possible obs: 100 % / Observed criterion σ(I): 2 / Redundancy: 5 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 12
Reflection shellResolution: 2.5→2.6 Å / Redundancy: 5 % / Rmerge(I) obs: 0.505 / Mean I/σ(I) obs: 2 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1FPU

1fpu


Resolution: 2.5→30 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.904 / SU B: 7.337 / SU ML: 0.168 / Cross valid method: THROUGHOUT / ESU R: 0.378 / ESU R Free: 0.257 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.246 1476 5.1 %RANDOM
Rwork0.207 ---
obs0.209 27517 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 33.97 Å2
Baniso -1Baniso -2Baniso -3
1-0.59 Å20.29 Å20 Å2
2--0.59 Å20 Å2
3----0.88 Å2
Refinement stepCycle: LAST / Resolution: 2.5→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4400 0 72 166 4638
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0224590
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.581.9786219
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5965537
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.78124.218211
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.24115803
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.9121522
X-RAY DIFFRACTIONr_chiral_restr0.0940.2653
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023480
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2070.22113
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3130.23118
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1530.2228
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1860.250
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1160.217
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
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: 2.5→2.56 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.324 101 -
Rwork0.28 2007 -
obs--99.62 %

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