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- PDB-4ewh: Co-crystal structure of ACK1 with inhibitor -

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Basic information

Entry
Database: PDB / ID: 4ewh
TitleCo-crystal structure of ACK1 with inhibitor
ComponentsActivated CDC42 kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Drug Design / Enzyme Inhibitors / 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 / epidermal growth factor receptor binding / small GTPase-mediated signal transduction / 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 / epidermal growth factor receptor binding / small GTPase-mediated signal transduction / 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-T77 / Activated CDC42 kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsLiu, J. / Walker, N. / Wang, Z.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Synthesis and optimization of substituted furo[2,3-d]-pyrimidin-4-amines and 7H-pyrrolo[2,3-d]pyrimidin-4-amines as ACK1 inhibitors.
Authors: Jiao, X. / Kopecky, D.J. / Liu, J. / Liu, J. / Jaen, J.C. / Cardozo, M.G. / Sharma, R. / Walker, N. / Wesche, H. / Li, S. / Farrelly, E. / Xiao, S.H. / Wang, Z. / Kayser, F.
History
DepositionApr 27, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 19, 2012Provider: repository / Type: Initial release
Revision 1.1Oct 31, 2012Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Activated CDC42 kinase 1
A: Activated CDC42 kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,9904
Polymers63,0072
Non-polymers9832
Water41423
1
A: Activated CDC42 kinase 1
hetero molecules

B: Activated CDC42 kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,9904
Polymers63,0072
Non-polymers9832
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555-x+1/2,y+1/2,-z1
Buried area1600 Å2
ΔGint-11 kcal/mol
Surface area24630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)201.202, 42.480, 71.031
Angle α, β, γ (deg.)90.000, 95.290, 90.000
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11B
21A
12A
22B

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1111B117 - 390
2111A117 - 390
1121A1 - 401
2121B1 - 401

NCS ensembles :
ID
1
2

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Components

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


Mass: 31503.285 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TNK2, ACK1
References: UniProt: Q07912, non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-T77 / 6-{4-[2-(dimethylamino)ethoxy]phenyl}-N-(1,3-dithiolan-2-ylmethyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine


Mass: 491.671 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H29N5OS2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 23 / 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: 2.4 Å3/Da / Density % sol: 48.72 %
Crystal growTemperature: 298 K / Method: vapor diffusion / Details: vapor diffusion, temperature 298K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2
DetectorType: ADSC QUANTUM 315 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.5→100.173 Å / Num. obs: 21086 / % possible obs: 99.8 % / Redundancy: 3.6 % / Rmerge(I) obs: 0.058 / Rsym value: 0.058 / Net I/σ(I): 16.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
2.5-2.643.60.4371.71108430480.43799.9
2.64-2.83.70.2792.71053228770.27999.9
2.8-2.993.60.193.8996327310.1999.9
2.99-3.233.70.1186.1928625340.118100
3.23-3.543.60.0710.1851423330.0799.9
3.54-3.953.60.04514.5777721330.04599.9
3.95-4.563.60.03318.5673718650.03399.8
4.56-5.593.60.03218.5572716010.03299.8
5.59-7.913.50.0317.8440312580.0399.7
7.91-60.4643.30.02720.623037060.02798.3

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Processing

Software
NameVersionClassificationNB
SCALA3.1.20data scaling
REFMAC5.1.24refinement
PDB_EXTRACT3.11data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→100 Å / Cor.coef. Fo:Fc: 0.908 / Cor.coef. Fo:Fc free: 0.857 / Occupancy max: 1 / Occupancy min: 1 / SU B: 12.788 / SU ML: 0.294 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.98 / ESU R Free: 0.378 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.3132 1082 5.1 %RANDOM
Rwork0.2557 ---
obs0.2588 21084 99.71 %-
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: 93.85 Å2 / Biso mean: 51.1283 Å2 / Biso min: 22.14 Å2
Baniso -1Baniso -2Baniso -3
1--1.76 Å20 Å21.29 Å2
2--3.52 Å20 Å2
3----1.52 Å2
Refinement stepCycle: LAST / Resolution: 2.5→100 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4411 0 68 23 4502
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.0214596
X-RAY DIFFRACTIONr_angle_refined_deg2.1371.986227
X-RAY DIFFRACTIONr_dihedral_angle_1_deg9.2615547
X-RAY DIFFRACTIONr_chiral_restr0.1250.2666
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.023488
X-RAY DIFFRACTIONr_nbd_refined0.2480.21947
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1870.2157
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.3670.264
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.3420.23
X-RAY DIFFRACTIONr_mcbond_it1.0131.52738
X-RAY DIFFRACTIONr_mcangle_it1.87624416
X-RAY DIFFRACTIONr_scbond_it2.50431858
X-RAY DIFFRACTIONr_scangle_it4.1694.51811
Refine LS restraints NCS

Dom-ID: 1 / Refine-ID: X-RAY DIFFRACTION

Ens-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
1B2202TIGHT POSITIONAL0.10.05
1B2202TIGHT THERMAL0.270.5
2A34TIGHT POSITIONAL0.070.05
2A34TIGHT THERMAL0.310.5
LS refinement shellResolution: 2.5→2.565 Å / Total num. of bins used: 20
RfactorNum. reflection
Rfree0.339 78
Rwork0.288 1458
all-1536

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