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- PDB-7b8w: Structure of LIMK1 Kinase domain with allosteric inhibitor TH-470 -

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Basic information

Entry
Database: PDB / ID: 7b8w
TitleStructure of LIMK1 Kinase domain with allosteric inhibitor TH-470
ComponentsLIM domain kinase 1
KeywordsSIGNALING PROTEIN / LIMK1 Kinase domain / inhibitor
Function / homology
Function and homology information


positive regulation of actin filament bundle assembly / RHO GTPases Activate ROCKs / Sema4D induced cell migration and growth-cone collapse / axon extension / stress fiber assembly / RHO GTPases activate PAKs / Fc-gamma receptor signaling pathway involved in phagocytosis / ubiquitin ligase inhibitor activity / Sema3A PAK dependent Axon repulsion / Rho protein signal transduction ...positive regulation of actin filament bundle assembly / RHO GTPases Activate ROCKs / Sema4D induced cell migration and growth-cone collapse / axon extension / stress fiber assembly / RHO GTPases activate PAKs / Fc-gamma receptor signaling pathway involved in phagocytosis / ubiquitin ligase inhibitor activity / Sema3A PAK dependent Axon repulsion / Rho protein signal transduction / positive regulation of axon extension / positive regulation of stress fiber assembly / heat shock protein binding / EPHB-mediated forward signaling / male germ cell nucleus / Regulation of actin dynamics for phagocytic cup formation / nervous system development / lamellipodium / actin cytoskeleton organization / eukaryotic translation initiation factor 2alpha kinase activity / cytoskeleton / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / postsynapse / protein kinase activity / neuron projection / nuclear speck / protein phosphorylation / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / ubiquitin protein ligase binding / glutamatergic synapse / signal transduction / ATP binding / metal ion binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
: / LIM zinc-binding domain signature. / LIM domain / Zinc-binding domain present in Lin-11, Isl-1, Mec-3. / Zinc finger, LIM-type / LIM domain profile. / PDZ domain / PDZ domain profile. / Domain present in PSD-95, Dlg, and ZO-1/2. / PDZ domain ...: / LIM zinc-binding domain signature. / LIM domain / Zinc-binding domain present in Lin-11, Isl-1, Mec-3. / Zinc finger, LIM-type / LIM domain profile. / PDZ domain / PDZ domain profile. / Domain present in PSD-95, Dlg, and ZO-1/2. / PDZ domain / PDZ superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-T3B / LIM domain kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.8 Å
AuthorsLee, H. / Yosaatmadja, Y. / Burgess-Brown, N.A. / von Delft, F. / Arrowsmith, C.H. / Edwards, A. / Bountra, C. / Elkins, J.M.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom) United Kingdom
CitationJournal: To Be Published
Title: Structure of LIMK1 Kinase domain with allosteric inhibitor TH-470
Authors: Lee, H. / Yosaatmadja, Y. / Burgess-Brown, N.A. / von Delft, F. / Arrowsmith, C.H. / Edwards, A. / Bountra, C. / Elkins, J.M.
History
DepositionDec 13, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 2, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: 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: LIM domain kinase 1
B: LIM domain kinase 1
C: LIM domain kinase 1
D: LIM domain kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)146,58811
Polymers143,9794
Non-polymers2,6097
Water1448
1
A: LIM domain kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7875
Polymers35,9951
Non-polymers7924
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: LIM domain kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6012
Polymers35,9951
Non-polymers6061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: LIM domain kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6012
Polymers35,9951
Non-polymers6061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: LIM domain kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6012
Polymers35,9951
Non-polymers6061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)84.692, 83.665, 96.513
Angle α, β, γ (deg.)90.000, 91.970, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
31C
41D

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1114A1 - 640
2114B1 - 640
3114C1 - 640
4114D1 - 640

NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.999959, -0.00746, 0.005147), (0.007535, -0.999862, 0.014785), (0.005036, 0.014824, 0.999877)42.527981, 47.372978, -0.43354
3given(-0.006859, 0.999924, 0.010257), (0.999834, 0.007031, -0.016783), (-0.016854, 0.010141, -0.999807)-24.87492, -37.525242, 48.890511
4given(0.003252, -0.999699, 0.024302), (0.999848, 0.003667, 0.017055), (-0.017139, 0.024243, 0.999559)23.997379, 3.38232, -48.08276

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Components

#1: Protein
LIM domain kinase 1 / LIMK-1


Mass: 35994.773 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LIMK1, LIMK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P53667, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-T3B / 2-(2-methylpropanoylamino)-~{N}-[2-[(phenylmethyl)-[4-(phenylsulfamoyl)phenyl]carbonyl-amino]ethyl]-1,3-thiazole-5-carboxamide


Mass: 605.728 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C30H31N5O5S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 8 / 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: 2.38 Å3/Da / Density % sol: 48.33 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / Details: 0.2M Ammonium Citrate dibasic, 20% w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.9686 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 28, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9686 Å / Relative weight: 1
ReflectionResolution: 2.8→51.2 Å / Num. obs: 33406 / % possible obs: 99.9 % / Redundancy: 6.8 % / CC1/2: 0.987 / Rmerge(I) obs: 0.221 / Rpim(I) all: 0.091 / Rrim(I) all: 0.239 / Net I/σ(I): 7 / Num. measured all: 225877 / Scaling rejects: 24
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.8-2.946.81.4523005443920.590.5951.571.699.9
9.29-51.26.30.08861029650.9880.0370.09515.999.3

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.38 Å50.1 Å
Translation3.38 Å50.1 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
Aimless0.7.4data scaling
PHASER2.8.3phasing
PDB_EXTRACT3.27data extraction
xia2data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5NXC

5nxc


Resolution: 2.8→50.15 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.858 / SU B: 18.604 / SU ML: 0.352 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.425 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2862 1574 4.7 %RANDOM
Rwork0.2057 ---
obs0.2094 31818 99.91 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 118.53 Å2 / Biso mean: 45.413 Å2 / Biso min: 24.34 Å2
Baniso -1Baniso -2Baniso -3
1--1.56 Å20 Å2-0.15 Å2
2---2.97 Å20 Å2
3---4.53 Å2
Refinement stepCycle: final / Resolution: 2.8→50.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8464 0 180 8 8652
Biso mean--42.79 30.55 -
Num. residues----1103
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0138872
X-RAY DIFFRACTIONr_bond_other_d0.0010.0178110
X-RAY DIFFRACTIONr_angle_refined_deg1.4251.64312067
X-RAY DIFFRACTIONr_angle_other_deg1.1651.57518542
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.68151092
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.03920.949432
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.125151318
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.2961557
X-RAY DIFFRACTIONr_chiral_restr0.0580.21138
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0210074
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022112
Refine LS restraints NCS

Ens-ID: 1 / Number: 3903 / Refine-ID: X-RAY DIFFRACTION

Dom-IDAuth asym-IDTypeRms dev position (Å)Weight position
1AMEDIUM POSITIONAL0.380.5
2BMEDIUM POSITIONAL0.390.5
3CMEDIUM POSITIONAL0.360.5
4DMEDIUM POSITIONAL0.440.5
1AMEDIUM THERMAL5.242
2BMEDIUM THERMAL4.32
3CMEDIUM THERMAL4.752
4DMEDIUM THERMAL5.762
LS refinement shellResolution: 2.8→2.873 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.388 116 -
Rwork0.34 2335 -
all-2451 -
obs--99.76 %

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