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- PDB-4id7: ACK1 kinase in complex with the inhibitor cis-3-[8-amino-1-(4-phe... -

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Basic information

Entry
Database: PDB / ID: 4id7
TitleACK1 kinase in complex with the inhibitor cis-3-[8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclobutanol
ComponentsActivated CDC42 kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


regulation of clathrin-dependent endocytosis / cytoophidium / Grb2-EGFR complex / GTPase inhibitor activity / WW domain binding / clathrin-coated vesicle / small GTPase-mediated signal transduction / epidermal growth factor receptor binding / clathrin-coated pit / protein serine/threonine/tyrosine kinase activity ...regulation of clathrin-dependent endocytosis / cytoophidium / Grb2-EGFR complex / GTPase inhibitor activity / WW domain binding / clathrin-coated vesicle / small GTPase-mediated signal transduction / epidermal growth factor receptor binding / clathrin-coated pit / protein serine/threonine/tyrosine kinase activity / adherens junction / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / cytoplasmic vesicle membrane / endocytosis / positive regulation of peptidyl-tyrosine phosphorylation / protein tyrosine kinase activity / cell surface receptor signaling pathway / non-specific serine/threonine protein kinase / endosome / phosphorylation / protein serine kinase activity / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / ubiquitin protein ligase binding / perinuclear region of cytoplasm / ATP binding / membrane / identical protein binding / metal ion binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Activated CDC42 kinase 1 / Cdc42 binding domain-like superfamily / : / Cdc42 binding domain-like / Mig-6 domain / GTPase binding / EGFR receptor inhibitor Mig-6 / Variant SH3 domain / Src homology 3 domains / SH3-like domain superfamily ...Activated CDC42 kinase 1 / Cdc42 binding domain-like superfamily / : / Cdc42 binding domain-like / Mig-6 domain / GTPase binding / EGFR receptor inhibitor Mig-6 / Variant SH3 domain / Src homology 3 domains / 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-1G0 / Activated CDC42 kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 3 Å
AuthorsJin, M. / Wang, J. / Kleinberg, A. / Kadalbajoo, M. / Siu, K. / Cooke, A. / Bittner, M. / Yao, Y. / Thelemann, A. / Ji, Q. ...Jin, M. / Wang, J. / Kleinberg, A. / Kadalbajoo, M. / Siu, K. / Cooke, A. / Bittner, M. / Yao, Y. / Thelemann, A. / Ji, Q. / Bhagwat, S. / Crew, A.P. / Pachter, J. / Epstein, D. / Mulvihill, M.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Discovery of potent, selective and orally bioavailable imidazo[1,5-a]pyrazine derived ACK1 inhibitors.
Authors: Jin, M. / Wang, J. / Kleinberg, A. / Kadalbajoo, M. / Siu, K.W. / Cooke, A. / Bittner, M.A. / Yao, Y. / Thelemann, A. / Ji, Q. / Bhagwat, S. / Mulvihill, K.M. / Rechka, J.A. / Pachter, J.A. ...Authors: Jin, M. / Wang, J. / Kleinberg, A. / Kadalbajoo, M. / Siu, K.W. / Cooke, A. / Bittner, M.A. / Yao, Y. / Thelemann, A. / Ji, Q. / Bhagwat, S. / Mulvihill, K.M. / Rechka, J.A. / Pachter, J.A. / Crew, A.P. / Epstein, D. / Mulvihill, M.J.
History
DepositionDec 11, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 30, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 13, 2013Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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: Activated CDC42 kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,6943
Polymers31,2251
Non-polymers4682
Water1086
1
A: Activated CDC42 kinase 1
hetero molecules

A: Activated CDC42 kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,3876
Polymers62,4502
Non-polymers9374
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation16_555-y+1/2,-x+1/2,-z+1/21
Buried area2010 Å2
ΔGint-45 kcal/mol
Surface area26260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)94.659, 94.659, 187.267
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number97
Space group name H-MI422

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Components

#1: Protein Activated CDC42 kinase 1 / ACK-1 / Tyrosine kinase non-receptor protein 2


Mass: 31225.092 Da / Num. of mol.: 1 / Fragment: Kinase domain, UNP residues 117-389
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACK1, TNK2
References: UniProt: Q07912, non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-1G0 / cis-3-[8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclobutanol


Mass: 372.420 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20N4O2
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 6 / 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: 3.41 Å3/Da / Density % sol: 64 %
Crystal growMethod: ligang replacement / Details: ligang replacement

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1.00001 / Wavelength: 1.00001 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Apr 10, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00001 Å / Relative weight: 1
ReflectionResolution: 3→93.63 Å / Num. obs: 8897 / % possible obs: 90.5 % / Observed criterion σ(I): 0 / Redundancy: 5 % / Rmerge(I) obs: 0.088 / Net I/σ(I): 7
Reflection shellResolution: 3→3.24 Å / Redundancy: 5.1 % / Rmerge(I) obs: 0.443 / Mean I/σ(I) obs: 1.7 / % possible all: 91.9

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Processing

Software
NameVersionClassificationNB
REFMAC5.5.0109refinement
PDB_EXTRACT3.11data extraction
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 3→46.81 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.908 / Occupancy max: 1 / Occupancy min: 0 / SU B: 37.987 / SU ML: 0.331 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.441 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2592 528 6.7 %RANDOM
Rwork0.2101 ---
obs0.2133 7925 89.07 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 85.31 Å2 / Biso mean: 81.704 Å2 / Biso min: 17.83 Å2
Baniso -1Baniso -2Baniso -3
1-2.39 Å20 Å20 Å2
2--2.39 Å20 Å2
3----4.78 Å2
Refinement stepCycle: LAST / Resolution: 3→46.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2153 0 33 6 2192
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0212145
X-RAY DIFFRACTIONr_bond_other_d0.0010.021475
X-RAY DIFFRACTIONr_angle_refined_deg1.0281.9742920
X-RAY DIFFRACTIONr_angle_other_deg0.97133528
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4155266
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.08323.15292
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.36315330
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.5211516
X-RAY DIFFRACTIONr_chiral_restr0.0590.2321
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0212401
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02449
X-RAY DIFFRACTIONr_mcbond_it0.85621334
X-RAY DIFFRACTIONr_mcbond_other0.1172539
X-RAY DIFFRACTIONr_mcangle_it1.61732127
X-RAY DIFFRACTIONr_scbond_it2.1554811
X-RAY DIFFRACTIONr_scangle_it3.4766791
LS refinement shellResolution: 3.002→3.08 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.39 42 -
Rwork0.329 527 -
all-569 -
obs--90.03 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.77850.63726.18936.8777-1.96639.94580.41760.098-0.8857-0.23710.0788-0.42421.46270.0825-0.49630.7334-0.06380.43540.23250.05820.641732.8017.94236.723
23.73380.0335-1.26052.7503-0.70695.4356-0.03570.1824-0.2412-0.0609-0.03080.16780.4331-0.13240.06660.2085-0.03860.02050.0736-0.03980.13436.76925.27918.908
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A117 - 207
2X-RAY DIFFRACTION2A208 - 389

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