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- PDB-9di9: Rat branched chain ketoacid dehydrogenase kinase in complex with ... -

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Basic information

Entry
Database: PDB / ID: 9di9
TitleRat branched chain ketoacid dehydrogenase kinase in complex with inhibitor
ComponentsBranched-chain alpha-ketoacid dehydrogenase kinase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / branch chain ketoacid dehydrogenase / branch chain ketoacid dehydrogenase kinase / inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


negative regulation of amino acid metabolic process / [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase / [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase activity / pyruvate dehydrogenase (acetyl-transferring) kinase activity / branched-chain amino acid catabolic process / oxoglutarate dehydrogenase complex / amino acid catabolic process / Branched-chain amino acid catabolism / lipid biosynthetic process / protein serine/threonine phosphatase activity ...negative regulation of amino acid metabolic process / [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase / [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase activity / pyruvate dehydrogenase (acetyl-transferring) kinase activity / branched-chain amino acid catabolic process / oxoglutarate dehydrogenase complex / amino acid catabolic process / Branched-chain amino acid catabolism / lipid biosynthetic process / protein serine/threonine phosphatase activity / regulation of glucose metabolic process / kinase activity / phosphorylation / non-specific serine/threonine protein kinase / mitochondrial matrix / protein serine/threonine kinase activity / protein serine kinase activity / mitochondrion / ATP binding
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 / Signal transduction histidine kinase-related protein, C-terminal / 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
: / ADENOSINE-5'-DIPHOSPHATE / : / PHOSPHATE ION / Branched-chain alpha-ketoacid dehydrogenase kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.155 Å
AuthorsLiu, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of First Branched-Chain Ketoacid Dehydrogenase Kinase (BDK) Inhibitor Clinical Candidate PF-07328948.
Authors: Filipski, K.J. / Martinez-Alsina, L.A. / Reese, M.R. / Evrard, E. / Buzon, L.M. / Cameron, K.O. / Zhang, Y. / Coffman, K.J. / Bradow, J. / Kormos, B.L. / Liu, S. / Knafels, J.D. / ...Authors: Filipski, K.J. / Martinez-Alsina, L.A. / Reese, M.R. / Evrard, E. / Buzon, L.M. / Cameron, K.O. / Zhang, Y. / Coffman, K.J. / Bradow, J. / Kormos, B.L. / Liu, S. / Knafels, J.D. / Sahasrabudhe, P.V. / Chen, J. / Kalgutkar, A.S. / Bessire, A.J. / Orozco, C.C. / Balesano, A. / Cerny, M.A. / Bollinger, E. / Reyes, A.R. / Laforest, B. / Rosado, A. / Williams, G. / Marshall, M. / Tam Neale, K. / Chen, X. / Hirenallur-Shanthappa, D. / Stansfield, J.C. / Groarke, J. / Qiu, R. / Karas, S. / Roth Flach, R.J. / Esler, W.P.
History
DepositionSep 5, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 4, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Branched-chain alpha-ketoacid dehydrogenase kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,2036
Polymers44,2621
Non-polymers9425
Water2,342130
1
A: Branched-chain alpha-ketoacid dehydrogenase kinase
hetero molecules

A: Branched-chain alpha-ketoacid dehydrogenase kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,40712
Polymers88,5232
Non-polymers1,88410
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555y,x,-z1
Buried area5720 Å2
ΔGint-64 kcal/mol
Surface area29640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)126.35, 126.35, 74.68
Angle α, β, γ (deg.)90, 90, 90
Int Tables number94
Space group name H-MP42212
Components on special symmetry positions
IDModelComponents
11A-611-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Branched-chain alpha-ketoacid dehydrogenase kinase / BCKDH kinase / BCKDHKIN / BDK / [3-methyl-2-oxobutanoate dehydrogenase [lipoamide]] kinase / mitochondrial


Mass: 44261.582 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCKDK / Production host: Escherichia coli (E. coli)
References: UniProt: O14874, non-specific serine/threonine protein kinase, [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase

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Non-polymers , 6 types, 135 molecules

#2: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: K
#5: Chemical ChemComp-A1A40 / (3M)-6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid


Mass: 356.292 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H8F4O3S / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 130 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 3.37 Å3/Da / Density % sol: 63.47 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 16% PEG-3350 and 8% tacsimate pH 6.0 (Hampton Research). Fully grown crystals were soaked overnight in a solution of 8% tacsimate pH 6.0, 25% PEG-3350, 50 mM KCl, 50 mM MgCl2, 2 mM ADP, 20% ...Details: 16% PEG-3350 and 8% tacsimate pH 6.0 (Hampton Research). Fully grown crystals were soaked overnight in a solution of 8% tacsimate pH 6.0, 25% PEG-3350, 50 mM KCl, 50 mM MgCl2, 2 mM ADP, 20% glycerol, 5% DMSO, and 1.5 mM 6 (PF-07328948) and flash frozen in liquid nitrogen

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 14, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.155→89.35 Å / Num. obs: 26167 / % possible obs: 86.8 % / Redundancy: 13.2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.103 / Rpim(I) all: 0.03 / Net I/σ(I): 15.6
Reflection shellResolution: 2.155→2.292 Å / Redundancy: 13.5 % / Rmerge(I) obs: 2.728 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 1308 / CC1/2: 0.439 / Rpim(I) all: 0.761 / % possible all: 46

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
XDSdata reduction
STARANISOdata scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.155→25.27 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.941 / SU R Cruickshank DPI: 0.202 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.207 / SU Rfree Blow DPI: 0.178 / SU Rfree Cruickshank DPI: 0.177
RfactorNum. reflection% reflectionSelection details
Rfree0.2357 1327 -RANDOM
Rwork0.2059 ---
obs0.2074 26142 78.8 %-
Displacement parametersBiso mean: 58.18 Å2
Baniso -1Baniso -2Baniso -3
1--1.4241 Å20 Å20 Å2
2---1.4241 Å20 Å2
3---2.8481 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: LAST / Resolution: 2.155→25.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2526 0 58 130 2714
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0072639HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.843580HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d928SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes465HARMONIC5
X-RAY DIFFRACTIONt_it2639HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion341SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2053SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.77
X-RAY DIFFRACTIONt_other_torsion17.94
LS refinement shellResolution: 2.155→2.23 Å
RfactorNum. reflection% reflection
Rfree0.3007 30 -
Rwork0.2973 --
obs--15.61 %
Refinement TLS params.Origin x: 29.5687 Å / Origin y: -1.8098 Å / Origin z: -10.3305 Å
111213212223313233
T-0.0884 Å2-0.003 Å20.0364 Å2--0.0879 Å20.0185 Å2---0.0564 Å2
L0.6319 °20.2834 °2-0.1713 °2-1.9643 °2-0.4268 °2--0.6114 °2
S-0.0409 Å °-0.2407 Å °0.011 Å °-0.2407 Å °-0.0021 Å °-0.0148 Å °0.011 Å °-0.0148 Å °0.043 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A27 - 374
2X-RAY DIFFRACTION1{ A|* }A401 - 501

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