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- PDB-4app: Crystal Structure of the Human p21-Activated Kinase 4 in Complex ... -

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Basic information

Entry
Database: PDB / ID: 4app
TitleCrystal Structure of the Human p21-Activated Kinase 4 in Complex with (S)-N-(5-(3-benzyl-1-methylpiperazine-4-carbonyl)-6,6-dimethyl-1,4,5, 6-tetrahydropyrrolo(3,4-c)pyrazol-3-yl)-3-phenoxybenzamide
ComponentsSERINE/THREONINE-PROTEIN KINASE PAK 4
KeywordsTRANSFERASE / PROTEIN KINASE
Function / homology
Function and homology information


dendritic spine development / cadherin binding involved in cell-cell adhesion / Activation of RAC1 / RHOV GTPase cycle / RHOJ GTPase cycle / RHOQ GTPase cycle / regulation of MAPK cascade / CDC42 GTPase cycle / RHOH GTPase cycle / RHOU GTPase cycle ...dendritic spine development / cadherin binding involved in cell-cell adhesion / Activation of RAC1 / RHOV GTPase cycle / RHOJ GTPase cycle / RHOQ GTPase cycle / regulation of MAPK cascade / CDC42 GTPase cycle / RHOH GTPase cycle / RHOU GTPase cycle / cellular response to organic cyclic compound / RHOG GTPase cycle / RAC2 GTPase cycle / RAC3 GTPase cycle / negative regulation of endothelial cell apoptotic process / cytoskeleton organization / RAC1 GTPase cycle / regulation of cell growth / adherens junction / positive regulation of angiogenesis / cell migration / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / cell cycle / phosphorylation / focal adhesion / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / Golgi apparatus / signal transduction / ATP binding / cytoplasm / cytosol
Similarity search - Function
p21 activated kinase binding domain / CRIB domain superfamily / P21-Rho-binding domain / CRIB domain profile. / P21-Rho-binding domain / CRIB domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 ...p21 activated kinase binding domain / CRIB domain superfamily / P21-Rho-binding domain / CRIB domain profile. / P21-Rho-binding domain / CRIB domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase domain / 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-N53 / Serine/threonine-protein kinase PAK 4
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsKnighton, D.D. / Deng, Y.L. / Wang, C. / Guo, C. / McAlpine, I. / Zhang, J. / Kephart, S. / Johnson, M.C. / Li, H. / Bouzida, D. ...Knighton, D.D. / Deng, Y.L. / Wang, C. / Guo, C. / McAlpine, I. / Zhang, J. / Kephart, S. / Johnson, M.C. / Li, H. / Bouzida, D. / Yang, A. / Dong, L. / Marakovits, J. / Tikhe, J. / Richardson, P. / Guo, L.C. / Kania, R. / Edwards, M.P. / Kraynov, E. / Christensen, J. / Piraino, J. / Lee, J. / Dagostino, E. / Del-Carmen, C. / Smeal, T. / Murray, B.W.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Discovery of Pyrroloaminopyrazoles as Novel Pak Inhibitors.
Authors: Guo, C. / Mcalpine, I. / Zhang, J. / Knighton, D.D. / Kephart, S. / Johnson, M.C. / Li, H. / Bouzida, D. / Yang, A. / Dong, L. / Marakovits, J. / Tikhe, J. / Richardson, P. / Guo, L.C. / ...Authors: Guo, C. / Mcalpine, I. / Zhang, J. / Knighton, D.D. / Kephart, S. / Johnson, M.C. / Li, H. / Bouzida, D. / Yang, A. / Dong, L. / Marakovits, J. / Tikhe, J. / Richardson, P. / Guo, L.C. / Kania, R. / Edwards, M.P. / Kraynov, E. / Christensen, J. / Piraino, J. / Lee, J. / Dagostino, E. / Del-Carmen, C. / Deng, Y.L. / Smeal, T. / Murray, B.W.
History
DepositionApr 4, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 6, 2012Provider: repository / Type: Initial release
Revision 1.1May 8, 2019Group: Data collection / Derived calculations ...Data collection / Derived calculations / Experimental preparation / Other
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status / struct_conn
Item: _exptl_crystal_grow.method / _exptl_crystal_grow.temp ..._exptl_crystal_grow.method / _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval / _struct_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: SERINE/THREONINE-PROTEIN KINASE PAK 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0823
Polymers33,4251
Non-polymers6572
Water3,279182
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.424, 64.995, 85.829
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein SERINE/THREONINE-PROTEIN KINASE PAK 4 / P21-ACTIVATED KINASE 4 / PAK-4


Mass: 33424.840 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 300-591
Source method: isolated from a genetically manipulated source
Details: S474 IS PHOSPHORYLATED / Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: O96013, EC: 2.7.1.37
#2: Chemical ChemComp-N53 / N-[6,6-dimethyl-5-[(2S)-4-methyl-2-(phenylmethyl)piperazin-1-yl]carbonyl-2,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-phenoxy-benzamide


Mass: 564.677 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H36N6O3
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 182 / 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: 2.15 Å3/Da / Density % sol: 42.87 % / Description: NONE
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: CRYSTALS WERE GROWN FROM THE HANGING DROP VAPOR DIFFUSION METHOD AT 21 DEGREES CELCIUS BY MIXING 3.6 MICROLITERS OF A 10 MG/ML PROTEIN SOLUTION WITH A RESERVIOR SOLUTION CONTAINING: 5% (W/V) ...Details: CRYSTALS WERE GROWN FROM THE HANGING DROP VAPOR DIFFUSION METHOD AT 21 DEGREES CELCIUS BY MIXING 3.6 MICROLITERS OF A 10 MG/ML PROTEIN SOLUTION WITH A RESERVIOR SOLUTION CONTAINING: 5% (W/V) MEPEG 5K, 0.1 M IMIDAZOLE AT PH 6.2, 0.1 M (NH4)2HPO4 AND 5MM DTT

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Data collection

DiffractionMean temperature: 92 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Oct 1, 2003 / Details: MIRRORS
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→15 Å / Num. obs: 15002 / % possible obs: 99 % / Observed criterion σ(I): 2 / Redundancy: 3.7 % / Biso Wilson estimate: 14.5 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 13
Reflection shellResolution: 2.2→2.25 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.3 / Mean I/σ(I) obs: 2.8 / % possible all: 91.7

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Processing

Software
NameVersionClassification
CNX2005refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→14.7 Å / Rfactor Rfree error: 0.011 / Data cutoff high absF: 350246.48 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.229 433 3 %RANDOM
Rwork0.188 ---
obs-14250 94.2 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 40.4337 Å2 / ksol: 0.394004 e/Å3
Displacement parametersBiso mean: 25.1 Å2
Baniso -1Baniso -2Baniso -3
1--1.38 Å20 Å20 Å2
2---5.3 Å20 Å2
3---6.68 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.3 Å0.22 Å
Luzzati d res low-5 Å
Luzzati sigma a0.24 Å0.21 Å
Refinement stepCycle: LAST / Resolution: 2.2→14.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2311 0 48 182 2541
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.8
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d22.2
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.75
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.261.5
X-RAY DIFFRACTIONc_mcangle_it1.972
X-RAY DIFFRACTIONc_scbond_it2.082
X-RAY DIFFRACTIONc_scangle_it2.962.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 2.2→2.34 Å / Rfactor Rfree error: 0.032 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.26 64 3 %
Rwork0.229 2071 -
obs--85.8 %

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