2BFC

Reactivity modulation of human branched-chain alpha-ketoacid dehydrogenase by an internal molecular switch


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.64 Å
  • R-Value Free: 0.159 
  • R-Value Work: 0.144 
  • R-Value Observed: 0.144 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

A Versatile Conformational Switch Regulates Reactivity in Human Branched-Chain Alpha-Ketoacid Dehydrogenase.

Machius, M.Wynn, R.M.Chuang, J.L.Li, J.Kluger, R.Yu, D.Tomchick, D.R.Brautigam, C.A.Chuang, D.T.

(2006) Structure 14: 287

  • DOI: https://doi.org/10.1016/j.str.2005.10.009
  • Primary Citation of Related Structures:  
    1WCI, 2BEU, 2BEV, 2BEW, 2BFB, 2BFC, 2BFD, 2BFE, 2BFF

  • PubMed Abstract: 

    The dehydrogenase/decarboxylase (E1b) component of the 4 MD human branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) is a thiamin diphosphate (ThDP)-dependent enzyme. We have determined the crystal structures of E1b with ThDP bound intermediates after decarboxylation of alpha-ketoacids. We show that a key tyrosine residue in the E1b active site functions as a conformational switch to reduce the reactivity of the ThDP cofactor through interactions with its thiazolium ring. The intermediates do not assume the often-postulated enamine state, but likely a carbanion state. The carbanion presumably facilitates the second E1b-catalyzed reaction, involving the transfer of an acyl moiety from the intermediate to a lipoic acid prosthetic group in the transacylase (E2b) component of the BCKDC. The tyrosine switch further remodels an E1b loop region to promote E1b binding to E2b. Our results illustrate the versatility of the tyrosine switch in coordinating the catalytic events in E1b by modulating the reactivity of reaction intermediates.


  • Organizational Affiliation

    Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA. mischa.machius@utsouthwestern.edu


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
2-OXOISOVALERATE DEHYDROGENASE ALPHA SUBUNIT400Homo sapiensMutation(s): 1 
EC: 1.2.4.4
UniProt & NIH Common Fund Data Resources
Find proteins for P12694 (Homo sapiens)
Explore P12694 
Go to UniProtKB:  P12694
PHAROS:  P12694
GTEx:  ENSG00000248098 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP12694
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
2-OXOISOVALERATE DEHYDROGENASE BETA SUBUNIT342Homo sapiensMutation(s): 0 
EC: 1.2.4.4
UniProt & NIH Common Fund Data Resources
Find proteins for P21953 (Homo sapiens)
Explore P21953 
Go to UniProtKB:  P21953
PHAROS:  P21953
GTEx:  ENSG00000083123 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP21953
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.64 Å
  • R-Value Free: 0.159 
  • R-Value Work: 0.144 
  • R-Value Observed: 0.144 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 145.341α = 90
b = 145.341β = 90
c = 69.185γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-02-16
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2019-03-06
    Changes: Data collection, Experimental preparation, Other
  • Version 1.3: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description