2E0A

Crystal structure of human pyruvate dehydrogenase kinase 4 in complex with AMPPNP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.86 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.196 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4.

Kukimoto-Niino, M.Tokmakov, A.Terada, T.Ohbayashi, N.Fujimoto, T.Gomi, S.Shiromizu, I.Kawamoto, M.Matsusue, T.Shirouzu, M.Yokoyama, S.

(2011) Acta Crystallogr D Biol Crystallogr 67: 763-773

  • DOI: https://doi.org/10.1107/S090744491102405X
  • Primary Citation of Related Structures:  
    2E0A, 2ZDX, 2ZDY

  • PubMed Abstract: 

    The mitochondrial pyruvate dehydrogenase complex (PDC) catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA. PDC activity is tightly regulated by four members of a family of pyruvate dehydrogenase kinase isoforms (PDK1-4), which phosphorylate and inactivate PDC. Recently, the development of specific inhibitors of PDK4 has become an especially important focus for the pharmaceutical management of diabetes and obesity. In this study, crystal structures of human PDK4 complexed with either AMPPNP, ADP or the inhibitor M77976 were determined. ADP-bound PDK4 has a slightly wider active-site cleft and a more disordered ATP lid compared with AMPPNP-bound PDK4, although both forms of PDK4 assume open conformations with a wider active-site cleft than that in the closed conformation of the previously reported ADP-bound PDK2 structure. M77976 binds to the ATP-binding pocket of PDK4 and causes local conformational changes with complete disordering of the ATP lid. M77976 binding also leads to a large domain rearrangement that further expands the active-site cleft of PDK4 compared with the ADP- and AMPPNP-bound forms. Biochemical analyses revealed that M77976 inhibits PDK4 with increased potency compared with the previously characterized PDK inhibitor radicicol. Thus, the present structures demonstrate for the first time the flexible and dynamic aspects of PDK4 in the open conformation and provide a basis for the development of novel inhibitors targeting the nucleotide-binding pocket of PDK4.


  • Organizational Affiliation

    RIKEN Systems and Structural Biology Center, Suehiro-cho, Tsurumi-ku, Yokohama, Japan.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Pyruvate dehydrogenase kinase isozyme 4
A, B
394Homo sapiensMutation(s): 0 
EC: 2.7.11.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q16654 (Homo sapiens)
Explore Q16654 
Go to UniProtKB:  Q16654
PHAROS:  Q16654
GTEx:  ENSG00000004799 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ16654
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.86 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.196 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.121α = 90
b = 68.456β = 101.05
c = 79.755γ = 90
Software Package:
Software NamePurpose
CNSrefinement
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2007-10-09
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2011-11-23
    Changes: Database references
  • Version 1.3: 2023-10-25
    Changes: Data collection, Database references, Derived calculations, Refinement description