6ET9

Structure of the acetoacetyl-CoA-thiolase/HMG-CoA-synthase complex from Methanothermococcus thermolithotrophicus at 2.75 A


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.75 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.192 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Archaeal acetoacetyl-CoA thiolase/HMG-CoA synthase complex channels the intermediate via a fused CoA-binding site.

Vogeli, B.Engilberge, S.Girard, E.Riobe, F.Maury, O.Erb, T.J.Shima, S.Wagner, T.

(2018) Proc Natl Acad Sci U S A 115: 3380-3385

  • DOI: https://doi.org/10.1073/pnas.1718649115
  • Primary Citation of Related Structures:  
    6ESQ, 6ET9

  • PubMed Abstract: 

    Many reactions within a cell are thermodynamically unfavorable. To efficiently run some of those endergonic reactions, nature evolved intermediate-channeling enzyme complexes, in which the products of the first endergonic reactions are immediately consumed by the second exergonic reactions. Based on this concept, we studied how archaea overcome the unfavorable first reaction of isoprenoid biosynthesis-the condensation of two molecules of acetyl-CoA to acetoacetyl-CoA catalyzed by acetoacetyl-CoA thiolases (thiolases). We natively isolated an enzyme complex comprising the thiolase and 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase (HMGCS) from a fast-growing methanogenic archaeon, Methanothermococcus thermolithotrophicus HMGCS catalyzes the second reaction in the mevalonate pathway-the exergonic condensation of acetoacetyl-CoA and acetyl-CoA to HMG-CoA. The 380-kDa crystal structure revealed that both enzymes are held together by a third protein (DUF35) with so-far-unknown function. The active-site clefts of thiolase and HMGCS form a fused CoA-binding site, which allows for efficient coupling of the endergonic thiolase reaction with the exergonic HMGCS reaction. The tripartite complex is found in almost all archaeal genomes and in some bacterial ones. In addition, the DUF35 proteins are also important for polyhydroxyalkanoate (PHA) biosynthesis, most probably by functioning as a scaffold protein that connects thiolase with 3-ketoacyl-CoA reductase. This natural and highly conserved enzyme complex offers great potential to improve isoprenoid and PHA biosynthesis in biotechnologically relevant organisms.


  • Organizational Affiliation

    Biochemistry and Synthetic Metabolism, Max Planck Institute for Terrestrial Microbiology, 35043 Marburg, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Acetyl-CoA acetyltransferase thiolase
A, B, C, D
392Methanothermococcus thermolithotrophicusMutation(s): 0 
EC: 2.3.1.9
UniProt
Find proteins for A0A384E138 (Methanothermococcus thermolithotrophicus)
Explore A0A384E138 
Go to UniProtKB:  A0A384E138
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA0A384E138
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Pfam DUF35
E, F, G, H
130Methanothermococcus thermolithotrophicusMutation(s): 0 
UniProt
Find proteins for A0A384E139 (Methanothermococcus thermolithotrophicus)
Explore A0A384E139 
Go to UniProtKB:  A0A384E139
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA0A384E139
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
HydroxyMethylGlutaryl-CoA synthase
I, J, K, L
349Methanothermococcus thermolithotrophicusMutation(s): 0 
EC: 2.3.3.10
UniProt
Find proteins for A0A384E143 (Methanothermococcus thermolithotrophicus)
Explore A0A384E143 
Go to UniProtKB:  A0A384E143
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA0A384E143
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
TRS
Query on TRS

Download Ideal Coordinates CCD File 
AA [auth D]
HA [auth F]
JA [auth G]
MA [auth H]
N [auth A]
AA [auth D],
HA [auth F],
JA [auth G],
MA [auth H],
N [auth A],
O [auth A],
P [auth A],
R [auth B],
S [auth B],
U [auth C],
X [auth C]
2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL
C4 H12 N O3
LENZDBCJOHFCAS-UHFFFAOYSA-O
GOL
Query on GOL

Download Ideal Coordinates CCD File 
CA [auth D]
RA [auth I]
SA [auth I]
VA [auth J]
XA [auth K]
CA [auth D],
RA [auth I],
SA [auth I],
VA [auth J],
XA [auth K],
YA [auth L]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
DA [auth E],
GA [auth F],
IA [auth G],
LA [auth H]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
K
Query on K

Download Ideal Coordinates CCD File 
BA [auth D]
OA [auth I]
PA [auth I]
Q [auth A]
T [auth B]
BA [auth D],
OA [auth I],
PA [auth I],
Q [auth A],
T [auth B],
UA [auth J],
V [auth C],
WA [auth K]
POTASSIUM ION
K
NPYPAHLBTDXSSS-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
EA [auth E]
FA [auth E]
KA [auth G]
NA [auth H]
QA [auth I]
EA [auth E],
FA [auth E],
KA [auth G],
NA [auth H],
QA [auth I],
W [auth C]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
MG
Query on MG

Download Ideal Coordinates CCD File 
Y [auth D]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
M [auth A],
TA [auth J],
Z [auth D]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.75 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.192 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 106.617α = 90
b = 144.014β = 90
c = 230.585γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-03-14
    Type: Initial release
  • Version 1.1: 2018-03-21
    Changes: Database references
  • Version 1.2: 2018-04-11
    Changes: Data collection, Database references