6HXQ

Structure of citryl-CoA synthetase from Hydrogenobacter thermophilus


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.91 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 

Starting Models: experimental
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This is version 1.4 of the entry. See complete history


Literature

Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle.

Verschueren, K.H.G.Blanchet, C.Felix, J.Dansercoer, A.De Vos, D.Bloch, Y.Van Beeumen, J.Svergun, D.Gutsche, I.Savvides, S.N.Verstraete, K.

(2019) Nature 568: 571-575

  • DOI: https://doi.org/10.1038/s41586-019-1095-5
  • Primary Citation of Related Structures:  
    6HXH, 6HXI, 6HXJ, 6HXK, 6HXL, 6HXM, 6HXN, 6HXO, 6HXP, 6HXQ, 6QCL, 6QFB

  • PubMed Abstract: 

    Across different kingdoms of life, ATP citrate lyase (ACLY, also known as ACL) catalyses the ATP-dependent and coenzyme A (CoA)-dependent conversion of citrate, a metabolic product of the Krebs cycle, to oxaloacetate and the high-energy biosynthetic precursor acetyl-CoA 1 . The latter fuels pivotal biochemical reactions such as the synthesis of fatty acids, cholesterol and acetylcholine 2 , and the acetylation of histones and proteins 3,4 . In autotrophic prokaryotes, ACLY is a hallmark enzyme of the reverse Krebs cycle (also known as the reductive tricarboxylic acid cycle), which fixates two molecules of carbon dioxide in acetyl-CoA 5,6 . In humans, ACLY links carbohydrate and lipid metabolism and is strongly expressed in liver and adipose tissue 1 and in cholinergic neurons 2,7 . The structural basis of the function of ACLY remains unknown. Here we report high-resolution crystal structures of bacterial, archaeal and human ACLY, and use distinct substrate-bound states to link the conformational plasticity of ACLY to its multistep catalytic itinerary. Such detailed insights will provide the framework for targeting human ACLY in cancer 8-11 and hyperlipidaemia 12,13 . Our structural studies also unmask a fundamental evolutionary relationship that links citrate synthase, the first enzyme of the oxidative Krebs cycle, to an ancestral tetrameric citryl-CoA lyase module that operates in the reverse Krebs cycle. This molecular transition marked a key step in the evolution of metabolism on Earth.


  • Organizational Affiliation

    Unit for Structural Biology, VIB Center for Inflammation Research, Ghent, Belgium.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Citryl-CoA synthetase small subunit
A, C
353Hydrogenobacter thermophilusMutation(s): 0 
Gene Names: ccsB
UniProt
Find proteins for Q75VW6 (Hydrogenobacter thermophilus)
Explore Q75VW6 
Go to UniProtKB:  Q75VW6
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ75VW6
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Citryl-CoA synthetase large subunit
B, D
429Hydrogenobacter thermophilusMutation(s): 0 
Gene Names: ccsA
UniProt
Find proteins for Q75VW8 (Hydrogenobacter thermophilus)
Explore Q75VW8 
Go to UniProtKB:  Q75VW8
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ75VW8
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
COA (Subject of Investigation/LOI)
Query on COA

Download Ideal Coordinates CCD File 
G [auth A],
K [auth C]
COENZYME A
C21 H36 N7 O16 P3 S
RGJOEKWQDUBAIZ-IBOSZNHHSA-N
FLC (Subject of Investigation/LOI)
Query on FLC

Download Ideal Coordinates CCD File 
H [auth B]CITRATE ANION
C6 H5 O7
KRKNYBCHXYNGOX-UHFFFAOYSA-K
PGE
Query on PGE

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
I [auth C],
J [auth C]
TRIETHYLENE GLYCOL
C6 H14 O4
ZIBGPFATKBEMQZ-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.91 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 118.495α = 90
b = 127.029β = 90
c = 143.797γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Research Foundation - FlandersBelgium1524918N

Revision History  (Full details and data files)

  • Version 1.0: 2019-04-10
    Type: Initial release
  • Version 1.1: 2019-04-17
    Changes: Data collection, Database references
  • Version 1.2: 2019-05-08
    Changes: Data collection, Database references
  • Version 1.3: 2024-01-24
    Changes: Data collection, Database references, Refinement description
  • Version 1.4: 2024-11-06
    Changes: Structure summary