4B3J

Crystal structure of Mycobacterium tuberculosis fatty acid beta- oxidation complex with CoenzymeA bound at the hydratase and thiolase active sites

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 

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Literature

Structure of Mycobacterial Beta-Oxidation Trifunctional Enzyme Reveals its Altered Assembly and Putative Substrate Channeling Pathway.

Venkatesan, R., Wierenga, R.K.

(2013) ACS Chem Biol 8: 1063

  • DOI: https://doi.org/10.1021/cb400007k
  • Primary Citation of Related Structures:  
    4B3H, 4B3I, 4B3J

  • PubMed Abstract: 

    The incidence of tuberculosis is increasing due to the appearance of new drug-resistant variants. A thorough understanding of the disease organism is essential in order to create more effective drugs. In an attempt to understand better the poorly studied lipid metabolism of Mycobacterium tuberculosis (Mtb), we identified and characterized its fatty acid β-oxidation complex (trifunctional enzyme (TFE)). TFE is an α(2)β(2) complex consisting of two types of polypeptides catalyzing three of the four reactions of the β-oxidation of fatty acids. The kinetic constants (k(cat) and K(m)) show that the complexed α chain is more active than the individual α chain. Crystal structures of Mtb TFE (mtTFE) reveal that the quaternary assembly is strikingly different from the already known Pseudomonas fragi TFE (pfTFE) assembly due to the presence of a helical insertion (LA5) in the mtTFE-β subunit. This helical insertion prevents the pfTFE mode of assembly, as it would clash with helix H9A of the TFE-α chain. The mtTFE assembly appears to be more rigid and results in a different substrate channeling path between the α and the β subunits. Structural comparisons suggest that the mtTFE active sites can accommodate bulkier fatty acyl chains than in pfTFE. Although another thiolase (FadA2), more closely related to human TFE-β/thiolase, is present in the Mtb genome, it does not form a complex with mtTFE-α. Extensive phylogenetic analyses show that there are at least four TFE subfamilies. Our studies highlight the molecular properties of mtTFE, significantly extending the structural knowledge on this type of very interesting multifunctional enzymes.

    • Organizational Affiliation: 

    Department of Biochemistry and Biocenter Oulu, University of Oulu, Oulu 90014, Finland.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
FATTY ACID BETA-OXIDATION COMPLEX ALPHA-CHAIN FADB
A, B
736Mycobacterium tuberculosis H37RvMutation(s): 0 
EC: 4.2.1.17 (PDB Primary Data), 1.1.1.35 (PDB Primary Data)
UniProt
Find proteins for O53872 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore O53872 
Go to UniProtKB:  O53872
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO53872
Sequence Annotations
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  • Reference Sequence
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(by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
FATTY ACID BETA-OXIDATION COMPLEX BETA-CHAIN FADA
C, D
403Mycobacterium tuberculosis H37RvMutation(s): 0 
EC: 2.3.1.9 (PDB Primary Data), 2.3.1 (UniProt)
UniProt
Find proteins for O53871 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore O53871 
Go to UniProtKB:  O53871
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO53871
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
COA
Query on COA
Download Ideal Coordinates CCD File 
HA [auth C],
O [auth A],
OA [auth D],
Y [auth B]		COENZYME A
C21 H36 N7 O16 P3 S
RGJOEKWQDUBAIZ-IBOSZNHHSA-N
ADP
Query on ADP
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IA [auth C],
PA [auth D]		ADENOSINE-5'-DIPHOSPHATE
C10 H15 N5 O10 P2
XTWYTFMLZFPYCI-KQYNXXCUSA-N
SO4
Query on SO4
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AA [auth C]
BA [auth C]
CA [auth C]
DA [auth C]
E [auth A]
AA [auth C],
BA [auth C],
CA [auth C],
DA [auth C],
E [auth A],
EA [auth C],
F [auth A],
FA [auth C],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
JA [auth D],
KA [auth D],
LA [auth D],
MA [auth D],
NA [auth D],
P [auth B],
Q [auth B],
R [auth B],
S [auth B],
T [auth B],
U [auth B],
V [auth B],
W [auth B],
Z [auth C]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL
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GA [auth C]
K [auth A]
L [auth A]
M [auth A]
N [auth A]
GA [auth C],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
QA [auth D],
X [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 248.3α = 90
b = 135.25β = 110.64
c = 118.58γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-03-27
    Type: Initial release
  • Version 1.1: 2013-05-29
    Changes: Database references
  • Version 1.2: 2024-05-08
    Changes: Data collection, Database references, Derived calculations, Other