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- PDB-3qc4: PDK1 in complex with DFG-OUT inhibitor xxx -

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Basic information

Entry
Database: PDB / ID: 3qc4
TitlePDK1 in complex with DFG-OUT inhibitor xxx
Components3-phosphoinositide-dependent protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / serine/threonine kinase / phosphorylation / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


3-phosphoinositide-dependent protein kinase activity / Activation of AKT2 / regulation of mast cell degranulation / negative regulation of toll-like receptor signaling pathway / type B pancreatic cell development / positive regulation of phospholipase activity / RSK activation / hyperosmotic response / regulation of canonical NF-kappaB signal transduction / positive regulation of vascular endothelial cell proliferation ...3-phosphoinositide-dependent protein kinase activity / Activation of AKT2 / regulation of mast cell degranulation / negative regulation of toll-like receptor signaling pathway / type B pancreatic cell development / positive regulation of phospholipase activity / RSK activation / hyperosmotic response / regulation of canonical NF-kappaB signal transduction / positive regulation of vascular endothelial cell proliferation / negative regulation of cardiac muscle cell apoptotic process / phospholipase activator activity / positive regulation of sprouting angiogenesis / Constitutive Signaling by AKT1 E17K in Cancer / CD28 dependent PI3K/Akt signaling / phospholipase binding / positive regulation of blood vessel endothelial cell migration / Role of LAT2/NTAL/LAB on calcium mobilization / Estrogen-stimulated signaling through PRKCZ / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / negative regulation of endothelial cell apoptotic process / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / extrinsic apoptotic signaling pathway / RHO GTPases activate PKNs / cellular response to epidermal growth factor stimulus / GPVI-mediated activation cascade / T cell costimulation / activation of protein kinase B activity / Integrin signaling / insulin-like growth factor receptor signaling pathway / positive regulation of release of sequestered calcium ion into cytosol / VEGFR2 mediated vascular permeability / VEGFR2 mediated cell proliferation / cell projection / calcium-mediated signaling / positive regulation of protein localization to plasma membrane / peptidyl-threonine phosphorylation / negative regulation of transforming growth factor beta receptor signaling pathway / negative regulation of protein kinase activity / epidermal growth factor receptor signaling pathway / CLEC7A (Dectin-1) signaling / FCERI mediated NF-kB activation / G beta:gamma signalling through PI3Kgamma / cellular response to insulin stimulus / positive regulation of angiogenesis / Regulation of TP53 Degradation / cell migration / Downstream TCR signaling / insulin receptor signaling pathway / PIP3 activates AKT signaling / cytoplasmic vesicle / actin cytoskeleton organization / protein autophosphorylation / postsynaptic density / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / intracellular signal transduction / protein phosphorylation / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
PDK1-type, PH domain / PDPK1 family / PH domain / PH-like domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. ...PDK1-type, PH domain / PDPK1 family / PH domain / PH-like domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic 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-MP7 / 3-phosphoinositide-dependent protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsArndt, J.W.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Discovery of a potent and highly selective PDK1 inhibitor via fragment-based drug discovery.
Authors: Erlanson, D.A. / Arndt, J.W. / Cancilla, M.T. / Cao, K. / Elling, R.A. / English, N. / Friedman, J. / Hansen, S.K. / Hession, C. / Joseph, I. / Kumaravel, G. / Lee, W.C. / Lind, K.E. / ...Authors: Erlanson, D.A. / Arndt, J.W. / Cancilla, M.T. / Cao, K. / Elling, R.A. / English, N. / Friedman, J. / Hansen, S.K. / Hession, C. / Joseph, I. / Kumaravel, G. / Lee, W.C. / Lind, K.E. / McDowell, R.S. / Miatkowski, K. / Nguyen, C. / Nguyen, T.B. / Park, S. / Pathan, N. / Penny, D.M. / Romanowski, M.J. / Scott, D. / Silvian, L. / Simmons, R.L. / Tangonan, B.T. / Yang, W. / Sun, L.
History
DepositionJan 15, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 20, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 3-phosphoinositide-dependent protein kinase 1
B: 3-phosphoinositide-dependent protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,4794
Polymers71,4462
Non-polymers1,0332
Water7,656425
1
A: 3-phosphoinositide-dependent protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,2392
Polymers35,7231
Non-polymers5161
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: 3-phosphoinositide-dependent protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,2392
Polymers35,7231
Non-polymers5161
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)183.147, 57.336, 83.694
Angle α, β, γ (deg.)90.00, 114.13, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein 3-phosphoinositide-dependent protein kinase 1 / hPDK1


Mass: 35722.922 Da / Num. of mol.: 2 / Fragment: kinase domain (UNP residues 51-359) / Mutation: E303A,K304A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDPK1, PDK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O15530, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-MP7 / 1-(3,4-difluorobenzyl)-2-oxo-N-{(1R)-2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]-1-phenylethyl}-1,2-dihydropyridine-3-carboxamide


Mass: 516.495 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H22F2N4O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 425 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsLIGAND MP7 NAMED COMPOUND 33 IN PRIMARY CITATION.

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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: 2.81 Å3/Da / Density % sol: 56.17 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 2 M ammonium sulfate, pH 7, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Aug 13, 2010
RadiationMonochromator: Kohzu HLD-4 Double Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 72110 / % possible obs: 98.3 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 4 % / Rmerge(I) obs: 0.065
Reflection shellResolution: 1.8→1.86 Å / % possible all: 97.8

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.5.0109refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→30.49 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.947 / SU B: 5.087 / SU ML: 0.071 / Cross valid method: THROUGHOUT / σ(F): 2 / ESU R: 0.102 / ESU R Free: 0.106 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.21321 3620 5 %RANDOM
Rwork0.17239 ---
obs0.17446 68387 98.04 %-
all-73398 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 40.295 Å2
Baniso -1Baniso -2Baniso -3
1--1.23 Å20 Å2-1.16 Å2
2--2.1 Å20 Å2
3----1.81 Å2
Refinement stepCycle: LAST / Resolution: 1.8→30.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4489 0 76 425 4990
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.030.0224697
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.2881.9976353
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3485558
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.823.78209
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.03215.036825
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.8291524
X-RAY DIFFRACTIONr_chiral_restr0.1910.2686
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.0213528
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.4471.52779
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.40424484
X-RAY DIFFRACTIONr_scbond_it3.64231918
X-RAY DIFFRACTIONr_scangle_it5.6124.51865
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.802→1.849 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.291 244 -
Rwork0.253 4973 -
obs--96.25 %
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)
19.3803-0.69713.05215.45280.91973.3057-0.4721-0.1371.1811-0.09620.5566-1.3252-0.02070.2031-0.08450.0693-0.00110.00540.1673-0.18540.53618.864938.525921.9757
20.84470.0532-0.14520.53320.16831.84280.0190.029-0.0107-0.0450.0441-0.0690.11510.1425-0.06310.07140.03610.02040.0902-0.01360.0435-3.182824.123722.2782
36.2711-1.82892.84684.87225.557110.74570.06360.2366-0.0168-0.22280.3831-0.3496-0.33790.7012-0.44660.1124-0.01490.00280.1678-0.0170.15027.12689.51945.851
413.4829-1.2221-1.61428.06580.57132.1730.14242.52231.8029-0.8254-0.3065-0.7917-0.07490.15740.16420.1752-0.00750.15650.62590.44430.489118.997254.927745.2782
57.3132-1.93981.99364.3852-1.23782.6782-0.1061.02821.2257-0.3555-0.2555-0.3986-0.32130.18280.36150.1926-0.0302-0.03070.16090.18810.31649.746955.681751.5559
60.93080.31680.5591.0820.26791.44970.03620.02890.05130.0665-0.0479-0.11370.02170.04260.01170.05750.0205-0.02470.03140.00130.07584.795535.102661.8392
716.30442.76260.09121.4899-3.08829.4311-0.2539-0.51170.5311-0.0683-0.2833-0.11720.10130.35470.53720.0578-0.00340.09020.2592-0.12010.251712.55133.199121.8765
87.47154.08084.71232.75081.85333.9965-0.1390.06760.1805-0.1515-0.1237-0.02230.00840.2030.26280.1493-0.01170.00270.18970.11380.17129.648549.254251.9179
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A76 - 163
2X-RAY DIFFRACTION2A164 - 359
3X-RAY DIFFRACTION3B51 - 55
4X-RAY DIFFRACTION4B76 - 118
5X-RAY DIFFRACTION5B127 - 163
6X-RAY DIFFRACTION6B164 - 359
7X-RAY DIFFRACTION7A1
8X-RAY DIFFRACTION8B2

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