4X28

Crystal structure of the ChsE4-ChsE5 complex from Mycobacterium tuberculosis


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.186 
  • R-Value Work: 0.151 
  • R-Value Observed: 0.153 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Unraveling Cholesterol Catabolism in Mycobacterium tuberculosis: ChsE4-ChsE5 alpha 2 beta 2 Acyl-CoA Dehydrogenase Initiates beta-Oxidation of 3-Oxo-cholest-4-en-26-oyl CoA.

Yang, M.Lu, R.Guja, K.E.Wipperman, M.F.St Clair, J.R.Bonds, A.C.Garcia-Diaz, M.Sampson, N.S.

(2015) ACS Infect Dis 1: 110-125

  • DOI: https://doi.org/10.1021/id500033m
  • Primary Citation of Related Structures:  
    4X28

  • PubMed Abstract: 

    The metabolism of host cholesterol by Mycobacterium tuberculosis ( Mtb ) is an important factor for both its virulence and pathogenesis, although how and why cholesterol metabolism is required is not fully understood. Mtb uses a unique set of catabolic enzymes that are homologous to those required for classical β-oxidation of fatty acids but are specific for steroid-derived substrates. Here, we identify and assign the substrate specificities of two of these enzymes, ChsE4-ChsE5 (Rv3504-Rv3505) and ChsE3 (Rv3573c), that carry out cholesterol side chain oxidation in Mtb. Steady-state assays demonstrate that ChsE4-ChsE5 preferentially catalyzes the oxidation of 3-oxo-cholest-4-en-26-oyl CoA in the first cycle of cholesterol side chain β-oxidation that ultimately yields propionyl-CoA, whereas ChsE3 specifically catalyzes the oxidation of 3-oxo-chol-4-en-24-oyl CoA in the second cycle of β-oxidation that generates acetyl-CoA. However, ChsE4-ChsE5 can catalyze the oxidation of 3-oxo-chol-4-en-24-oyl CoA as well as 3-oxo-4-pregnene-20-carboxyl-CoA. The functional redundancy of ChsE4-ChsE5 explains the in vivo phenotype of the igr knockout strain of Mycobacterium tuberculosis ; the loss of ChsE1-ChsE2 can be compensated for by ChsE4-ChsE5 during the chronic phase of infection. The X-ray crystallographic structure of ChsE4-ChsE5 was determined to a resolution of 2.0 Å and represents the first high-resolution structure of a heterotetrameric acyl-CoA dehydrogenase (ACAD). Unlike typical homotetrameric ACADs that bind four flavin adenine dinucleotide (FAD) cofactors, ChsE4-ChsE5 binds one FAD at each dimer interface, resulting in only two substrate-binding sites rather than the classical four active sites. A comparison of the ChsE4-ChsE5 substrate-binding site to those of known mammalian ACADs reveals an enlarged binding cavity that accommodates steroid substrates and highlights novel prospects for designing inhibitors against the committed β-oxidation step in the first cycle of cholesterol side chain degradation by Mtb .


  • Organizational Affiliation

    Department of Chemistry, Department of Pharmacological Sciences, and Biochemistry and Structural Biology Graduate Program, Stony Brook University , Stony Brook, New York 11794, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Acyl-CoA dehydrogenase
A, B
400Mycobacterium tuberculosis H37RvMutation(s): 0 
Gene Names: fadE26Rv3504RVBD_3504LH57_19105P425_03646
UniProt
Find proteins for I6YCA3 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore I6YCA3 
Go to UniProtKB:  I6YCA3
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupI6YCA3
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Acyl-CoA dehydrogenaseC [auth D],
D [auth C]
373Mycobacterium tuberculosis H37RvMutation(s): 0 
Gene Names: fadE27Rv3505RVBD_3505LH57_19110P425_03647
UniProt
Find proteins for I6Y3Q0 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore I6Y3Q0 
Go to UniProtKB:  I6Y3Q0
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupI6Y3Q0
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FDA
Query on FDA

Download Ideal Coordinates CCD File 
E [auth A],
F [auth B]
DIHYDROFLAVINE-ADENINE DINUCLEOTIDE
C27 H35 N9 O15 P2
YPZRHBJKEMOYQH-UYBVJOGSSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
MSE
Query on MSE
A, B
L-PEPTIDE LINKINGC5 H11 N O2 SeMET
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.186 
  • R-Value Work: 0.151 
  • R-Value Observed: 0.153 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 185.745α = 90
b = 108.095β = 93.04
c = 82.019γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
SHARPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesR01-GM100021
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)United StatesF30-ES022930

Revision History  (Full details and data files)

  • Version 1.0: 2015-02-18
    Type: Initial release
  • Version 1.1: 2015-07-22
    Changes: Database references
  • Version 1.2: 2017-09-20
    Changes: Author supporting evidence, Derived calculations, Source and taxonomy, Structure summary
  • Version 1.3: 2019-12-18
    Changes: Author supporting evidence