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- PDB-7kp6: Structure of Ack1 kinase in complex with a selective inhibitor -

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Basic information

Entry
Database: PDB / ID: 7kp6
TitleStructure of Ack1 kinase in complex with a selective inhibitor
ComponentsActivated CDC42 kinase 1
KeywordsTRANSFERASE/INHIBITOR / protein-inhibitor complex / tyrosine kinase / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


regulation of clathrin-dependent endocytosis / Grb2-EGFR complex / GTPase inhibitor activity / cytoophidium / Signaling by LTK / clathrin-coated vesicle / epidermal growth factor receptor binding / small GTPase-mediated signal transduction / WW domain binding / phosphorylation ...regulation of clathrin-dependent endocytosis / Grb2-EGFR complex / GTPase inhibitor activity / cytoophidium / Signaling by LTK / clathrin-coated vesicle / epidermal growth factor receptor binding / small GTPase-mediated signal transduction / WW domain binding / phosphorylation / clathrin-coated pit / protein serine/threonine/tyrosine kinase activity / non-specific protein-tyrosine kinase / adherens junction / 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 / intracellular membrane-bounded organelle / protein serine kinase activity / protein serine/threonine kinase activity / ubiquitin protein ligase binding / perinuclear region of cytoplasm / ATP binding / identical protein binding / membrane / nucleus / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Activated CDC42 kinase 1 / Cdc42 binding domain-like superfamily / : / SAM domain-like / Cdc42 binding domain-like / Mig-6 domain / : / GTPase binding / EGFR receptor inhibitor Mig-6 / Variant SH3 domain ...Activated CDC42 kinase 1 / Cdc42 binding domain-like superfamily / : / SAM domain-like / 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 / 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-WTP / Activated CDC42 kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.79 Å
AuthorsThakur, M.K. / Miller, W.T. / Mahajan, N. / Seeliger, M.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)r35 gm119437 United States
CitationJournal: Nat Commun / Year: 2022
Title: Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance.
Authors: Sridaran, D. / Chouhan, S. / Mahajan, K. / Renganathan, A. / Weimholt, C. / Bhagwat, S. / Reimers, M. / Kim, E.H. / Thakur, M.K. / Saeed, M.A. / Pachynski, R.K. / Seeliger, M.A. / Miller, W. ...Authors: Sridaran, D. / Chouhan, S. / Mahajan, K. / Renganathan, A. / Weimholt, C. / Bhagwat, S. / Reimers, M. / Kim, E.H. / Thakur, M.K. / Saeed, M.A. / Pachynski, R.K. / Seeliger, M.A. / Miller, W.T. / Feng, F.Y. / Mahajan, N.P.
History
DepositionNov 10, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 9, 2022Provider: repository / Type: Initial release
Revision 1.1May 25, 2022Group: Database references / Structure summary / Category: audit_author / citation_author / Item: _audit_author.name / _citation_author.name
Revision 2.0Apr 19, 2023Group: Atomic model / Database references / Category: atom_site / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 2.1Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)65,8686
Polymers64,9912
Non-polymers8774
Water5,026279
1
A: Activated CDC42 kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9694
Polymers32,4951
Non-polymers4743
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Activated CDC42 kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8982
Polymers32,4951
Non-polymers4031
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)71.016, 42.819, 92.623
Angle α, β, γ (deg.)90.000, 99.650, 90.000
Int Tables number4
Space group name H-MP1211
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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


Mass: 32495.445 Da / Num. of mol.: 2 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TNK2, ACK1 / Plasmid: pFastbac HTb / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q07912, non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-WTP / 5-chloro-N~2~-[4-(4-methylpiperazin-1-yl)phenyl]-N~4~-{[(2R)-oxolan-2-yl]methyl}pyrimidine-2,4-diamine


Mass: 402.921 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H27ClN6O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 279 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.19 Å3/Da / Density % sol: 43.76 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 6.5
Details: 50mM Bis-Tris (pH 6.5), 23 % (w/v) polyethylene glycol 3350, 100 mM MgCl2, and 2.5% Glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.92009 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Feb 26, 2019
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92009 Å / Relative weight: 1
ReflectionResolution: 1.444→60.69 Å / Num. obs: 129549 / % possible obs: 94.4 % / Redundancy: 3.3 % / CC1/2: 0.997 / Rmerge(I) obs: 0.062 / Rrim(I) all: 0.074 / Net I/σ(I): 9.9
Reflection shellResolution: 1.444→1.624 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.531 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 3138 / CC1/2: 0.65 / % possible all: 78.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4HZR

4hzr


Resolution: 1.79→41.564 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 20.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2033 2515 5.08 %
Rwork0.1779 47004 -
obs0.1792 49519 94.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 156.87 Å2 / Biso mean: 32.4276 Å2 / Biso min: 7.81 Å2
Refinement stepCycle: final / Resolution: 1.79→41.564 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4268 0 114 279 4661
Biso mean--36.84 27.54 -
Num. residues----533
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0044456
X-RAY DIFFRACTIONf_angle_d0.776034
X-RAY DIFFRACTIONf_chiral_restr0.048653
X-RAY DIFFRACTIONf_plane_restr0.004770
X-RAY DIFFRACTIONf_dihedral_angle_d12.1782705
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.79-1.82440.25031370.2417262497
1.8244-1.86170.26581280.22912746100
1.8617-1.90220.28371440.2249265798
1.9022-1.94640.2905290.229362823
1.9464-1.99510.22491500.20432702100
1.9951-2.0490.2081630.19432710100
2.049-2.10930.23281330.19062736100
2.1093-2.17740.22611470.18462749100
2.1774-2.25520.18761570.17732739100
2.2552-2.34550.21981310.17842710100
2.3455-2.45220.19541560.17982724100
2.4522-2.58150.22951400.1802274799
2.5815-2.74320.20911600.18072750100
2.7432-2.9550.21811560.18612723100
2.955-3.25220.19621460.1797276099
3.2522-3.72260.17551450.1673276999
3.7226-4.6890.15871530.1383263895
4.689-41.5640.21171400.1753289299
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)
11.5945-1.18541.46143.1822-0.47943.92420.20080.2459-0.2039-0.4395-0.1308-0.04640.31180.3155-0.04110.30050.01440.02020.3953-0.02190.176424.135632.143212.216
20.8522-1.0817-0.92731.3840.94285.73560.01440.24580.0147-0.5132-0.10680.1621-0.68230.20210.09170.293-0.0424-0.02850.24530.03350.149621.80938.754515.7767
31.00290.20340.97210.6879-0.36024.0588-0.00950.1469-0.142-0.1091-0.019-0.15980.090.27750.02820.15650.05610.02380.1719-0.0080.143327.89228.53930.9515
44.8139-2.96674.62046.0533-4.47548.02450.04180.10340.1495-0.2294-0.06390.0507-0.14410.26210.05260.1203-0.01510.00220.0766-0.01430.104220.291641.469734.676
50.54260.7706-0.24681.99570.64151.1879-0.1870.12640.2857-0.36470.04950.3209-0.2082-0.02420.02390.2230.0088-0.05420.12560.00720.183212.069336.500426.3083
63.36160.0841.20931.8747-0.0831.5151-0.02860.00360.0417-0.133-0.04570.1840.0202-0.13020.08560.0960.0041-0.00030.0782-0.01950.11757.069231.184133.7413
75.31712.33950.82681.74340.33551.19240.1917-0.3479-0.46680.1049-0.11630.08530.2581-0.1653-0.06240.1611-0.02340.00030.11940.01120.14496.287122.578441.1314
83.42940.16170.572.9184-0.20263.2640.0831-0.39570.10230.114-0.13770.13390.1041-0.14150.04420.1078-0.00580.03030.138-0.03720.10879.497834.703646.1713
94.7491-0.2215.67691.81710.16426.89010.1731-0.2290.3834-0.0571-0.2469-0.1382-0.0385-0.07850.08280.1645-0.03530.00650.136-0.02880.20919.053144.714243.0252
102.3408-1.39160.52274.323-1.37663.26220.0135-0.14960.03040.27010.0170.3268-0.2472-0.3822-0.02660.3215-0.01860.04910.3986-0.00180.157312.220946.5801-0.5111
110.8561-0.0095-0.051.378-0.57432.52050.0503-0.23650.01370.1271-0.0845-0.0101-0.02230.23510.01410.1429-0.0320.0060.24120.0220.153518.996444.712-14.9792
121.9527-0.19360.21692.778-0.43662.33840.0053-0.1875-0.2085-0.02120.01820.10370.2960.0009-0.00470.1249-0.00240.01030.11660.03640.134315.507435.6124-25.8032
133.81050.3996-0.18952.2874-0.44171.5472-0.02840.0873-0.1407-0.25250.0054-0.04390.08270.14940.01610.1670.01470.01790.12820.00460.118718.093138.892-33.4124
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 117 through 181 )A117 - 181
2X-RAY DIFFRACTION2chain 'A' and (resid 182 through 201 )A182 - 201
3X-RAY DIFFRACTION3chain 'A' and (resid 202 through 225 )A202 - 225
4X-RAY DIFFRACTION4chain 'A' and (resid 226 through 246 )A226 - 246
5X-RAY DIFFRACTION5chain 'A' and (resid 247 through 288 )A247 - 288
6X-RAY DIFFRACTION6chain 'A' and (resid 289 through 324 )A289 - 324
7X-RAY DIFFRACTION7chain 'A' and (resid 325 through 345 )A325 - 345
8X-RAY DIFFRACTION8chain 'A' and (resid 346 through 377 )A346 - 377
9X-RAY DIFFRACTION9chain 'A' and (resid 378 through 391 )A378 - 391
10X-RAY DIFFRACTION10chain 'B' and (resid 118 through 181 )B118 - 181
11X-RAY DIFFRACTION11chain 'B' and (resid 182 through 292 )B182 - 292
12X-RAY DIFFRACTION12chain 'B' and (resid 293 through 324 )B293 - 324
13X-RAY DIFFRACTION13chain 'B' and (resid 325 through 389 )B325 - 389

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