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- PDB-7vbu: Crystal structure of human pyruvate dehydrogenase kinase 2 in com... -

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Basic information

Entry
Database: PDB / ID: 7vbu
TitleCrystal structure of human pyruvate dehydrogenase kinase 2 in complex with compound 5
Components[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
KeywordsTRANSFERASE/INHIBITOR / PDHK / KINASE INHIBITORS / FRAGMENT SCREENING / PDK1 / PDK2 / PDK3 / PDK4 / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


[pyruvate dehydrogenase (acetyl-transferring)] kinase / regulation of acetyl-CoA biosynthetic process from pyruvate / pyruvate dehydrogenase (acetyl-transferring) kinase activity / : / regulation of cellular ketone metabolic process / regulation of pH / cellular response to nutrient / Regulation of pyruvate dehydrogenase (PDH) complex / Signaling by Retinoic Acid / regulation of gluconeogenesis ...[pyruvate dehydrogenase (acetyl-transferring)] kinase / regulation of acetyl-CoA biosynthetic process from pyruvate / pyruvate dehydrogenase (acetyl-transferring) kinase activity / : / regulation of cellular ketone metabolic process / regulation of pH / cellular response to nutrient / Regulation of pyruvate dehydrogenase (PDH) complex / Signaling by Retinoic Acid / regulation of gluconeogenesis / intrinsic apoptotic signaling pathway by p53 class mediator / regulation of glucose metabolic process / regulation of calcium-mediated signaling / cellular response to reactive oxygen species / glucose metabolic process / glucose homeostasis / insulin receptor signaling pathway / protein kinase activity / mitochondrial matrix / phosphorylation / protein homodimerization activity / mitochondrion / nucleoplasm / ATP binding / cytosol
Similarity search - Function
Branched-chain alpha-ketoacid dehydrogenase kinase/Pyruvate dehydrogenase kinase, N-terminal / Alpha-ketoacid/pyruvate dehydrogenase kinase, N-terminal domain superfamily / PDK/BCKDK protein kinase / Mitochondrial branched-chain alpha-ketoacid dehydrogenase kinase / Histidine kinase domain / Histidine kinase domain profile. / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily
Similarity search - Domain/homology
8-cyclopropyl-2-methyl-9H-pyrido[2,3-b]indole / ACETATE ION / [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.89 Å
AuthorsOrita, T. / Doi, S. / Iwanaga, T. / Fujishima, A. / Adachi, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem. / Year: 2021
Title: Structure-based drug design of novel and highly potent pyruvate dehydrogenase kinase inhibitors.
Authors: Bessho, Y. / Akaki, T. / Hara, Y. / Yamakawa, M. / Obika, S. / Mori, G. / Ubukata, M. / Yasue, K. / Nakane, Y. / Terasako, Y. / Orita, T. / Doi, S. / Iwanaga, T. / Fujishima, A. / Adachi, T. ...Authors: Bessho, Y. / Akaki, T. / Hara, Y. / Yamakawa, M. / Obika, S. / Mori, G. / Ubukata, M. / Yasue, K. / Nakane, Y. / Terasako, Y. / Orita, T. / Doi, S. / Iwanaga, T. / Fujishima, A. / Adachi, T. / Ueno, H. / Motomura, T.
History
DepositionSep 1, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 16, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 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

Downloads & links

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Assembly

Deposited unit
A: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,2398
Polymers44,6481
Non-polymers5917
Water2,540141
1
A: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
hetero molecules

A: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,47816
Polymers89,2952
Non-polymers1,18214
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_665-x+1,-y+1,z1
Buried area5190 Å2
ΔGint-34 kcal/mol
Surface area29960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.462, 109.462, 84.093
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number172
Space group name H-MP64
Space group name HallP64
Symmetry operation#1: x,y,z
#2: x-y,x,z+2/3
#3: y,-x+y,z+1/3
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: -x,-y,z

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Components

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Protein , 1 types, 1 molecules A

#1: Protein [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial / Pyruvate dehydrogenase kinase isoform 2 / PDH kinase 2 / PDKII


Mass: 44647.730 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDK2, PDHK2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: Q15119, [pyruvate dehydrogenase (acetyl-transferring)] kinase

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Non-polymers , 5 types, 148 molecules

#2: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-6I4 / 8-cyclopropyl-2-methyl-9H-pyrido[2,3-b]indole


Mass: 222.285 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H14N2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 141 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.26 Å3/Da / Density % sol: 62.24 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 50 mM Na acetate pH 5.5, 100 mM magnesium chloride and 8% (v/v) isopropanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Apr 22, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.89→94.8 Å / Num. obs: 45254 / % possible obs: 98.5 % / Redundancy: 10.2 % / Biso Wilson estimate: 38.1 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.062 / Rpim(I) all: 0.02 / Rrim(I) all: 0.066 / Net I/σ(I): 18.5
Reflection shellResolution: 1.89→1.94 Å / Redundancy: 10.4 % / Rmerge(I) obs: 1.201 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 3309 / CC1/2: 0.768 / Rpim(I) all: 0.387 / Rrim(I) all: 1.262 / % possible all: 98.4

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
DIALSdata reduction
Aimlessdata scaling
Cootmodel building
PHENIXphenix.refinephasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7EBH

7ebh


Resolution: 1.89→94.8 Å / SU ML: 0.2489 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.1276
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1972 2203 4.87 %
Rwork0.185 43037 -
obs0.1856 45240 98.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 48.34 Å2
Refinement stepCycle: LAST / Resolution: 1.89→94.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2727 0 38 141 2906
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00242863
X-RAY DIFFRACTIONf_angle_d0.51613877
X-RAY DIFFRACTIONf_chiral_restr0.0412423
X-RAY DIFFRACTIONf_plane_restr0.0033498
X-RAY DIFFRACTIONf_dihedral_angle_d9.92411067
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.89-1.930.39481490.31442647X-RAY DIFFRACTION98.55
1.93-1.970.26241110.26842712X-RAY DIFFRACTION98.6
1.97-2.020.25861440.23122691X-RAY DIFFRACTION98.61
2.02-2.080.24771450.22062673X-RAY DIFFRACTION98.77
2.08-2.140.22471440.21692658X-RAY DIFFRACTION98.77
2.14-2.210.25121090.21922679X-RAY DIFFRACTION96.64
2.21-2.290.25991190.21762667X-RAY DIFFRACTION97.17
2.29-2.380.22421390.18832715X-RAY DIFFRACTION99.41
2.38-2.490.18861620.19372665X-RAY DIFFRACTION99.09
2.49-2.620.20331550.18812708X-RAY DIFFRACTION99.51
2.62-2.780.20911190.20242740X-RAY DIFFRACTION99.58
2.78-30.2381610.19812595X-RAY DIFFRACTION95.59
3-3.30.18181530.1882701X-RAY DIFFRACTION99.72
3.3-3.780.18151440.17362746X-RAY DIFFRACTION99.83
3.78-4.760.1711150.15212693X-RAY DIFFRACTION96.63
4.76-94.80.16861340.17532747X-RAY DIFFRACTION97.99
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)
10.758392573041-0.7343042445240.5375437600410.95715107213-1.136399334453.533590182680.0839883078221-0.1434724847020.3125151745860.7924290701190.0324433540332-0.384206624091-1.342459273750.2959414082820.7813469254470.702335727328-0.0554225100558-0.2339387668460.453119405734-0.02156354672390.52228800822654.788996019556.449361899685.4509907766
21.723731957810.891065683360.1334467840614.125206343740.07380150438951.8604759113-0.064190276845-0.231535201392-0.08596666322010.684889478988-0.0345572347554-0.666869986958-0.01779842715560.352711243498-0.2175241880540.5625785594460.0422714929771-0.2189533236110.4455350736050.02939894440970.51453119306856.613043995944.049761051685.3338721732
31.21746990645-0.8260174660451.065356038412.839194706220.07201740013061.495401008530.0180391452205-0.1777726819990.05893747697980.6480357996840.0378906437743-0.0200147748366-0.200392911566-0.077344059171-0.0009631475075710.4216110370480.0360345272997-0.09560736397810.3208536409030.006217518363420.34328181845347.304691929545.030684565979.6364782167
43.554767906470.621988866398-0.7977844204391.600198742450.6367017785171.14692762286-0.1039586735790.886897714298-0.104173353511-0.180631474370.106771494193-0.401280442733-0.1569641881950.187875749903-0.3288740091120.325098171020.01911224143790.01136082818120.586092028090.01676260583090.39174323008247.200997017548.533682179455.6705397613
54.61607449831.221770694460.4429934986563.70542689510.8795055809552.52470996663-0.1511100650270.937246562198-0.6046532864260.07382091693210.109746147187-0.3459545560850.1884862902730.113025391506-0.7387841231650.2291043085850.02561680850120.05555830446340.459737529862-0.1328001066180.27787444991838.993042691740.751451695757.2793306783
63.873685918810.289020499433-0.160906998321.2491620278-0.005921516716280.5609662814870.0330357223050.269980608961-0.3932342129280.409464130797-0.0158629558584-0.171237595466-0.01069133939190.137256459439-0.02506095193060.3140240846230.0450831756294-0.003698038388310.306459116878-0.04059391579110.24642633233830.964243394240.632168560664.2527814949
73.740550439590.5586486036461.220419345532.047384388250.6687852288452.59923680640.0867173326359-0.0852445348301-0.07520547274310.57724421284-0.104294387798-0.1347907488630.158515253511-0.02204298240110.006111480051040.3749060628620.0636039952034-0.01381127626310.3027287808230.00436187943380.26349209819237.757941019346.211426732870.464238572
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 14 through 42 )14 - 421 - 29
22chain 'A' and (resid 43 through 144 )43 - 14430 - 131
33chain 'A' and (resid 145 through 175 )145 - 175132 - 162
44chain 'A' and (resid 176 through 241 )176 - 241163 - 221
55chain 'A' and (resid 242 through 282 )242 - 282222 - 262
66chain 'A' and (resid 283 through 304 )283 - 304263 - 284
77chain 'A' and (resid 305 through 374 )305 - 374285 - 340

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