7YY9

Crystal structure of Mycobacterium abscessus Phosphopantetheine adenylyltransferase in complex with Fragment 13


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.49 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.206 

Starting Model: experimental
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Literature

Structural Characterization of Mycobacterium abscessus Phosphopantetheine Adenylyl Transferase Ligand Interactions: Implications for Fragment-Based Drug Design.

Thomas, S.E.McCarthy, W.J.El Bakali, J.Brown, K.P.Kim, S.Y.Blaszczyk, M.Mendes, V.Abell, C.Floto, R.A.Coyne, A.G.Blundell, T.L.

(2022) Front Mol Biosci 9: 880432-880432

  • DOI: https://doi.org/10.3389/fmolb.2022.880432
  • Primary Citation of Related Structures:  
    7YWM, 7YXZ, 7YY0, 7YY1, 7YY2, 7YY3, 7YY4, 7YY5, 7YY6, 7YY7, 7YY8, 7YY9, 7YYA, 7YYB, 7YYC

  • PubMed Abstract: 

    Anti-microbial resistance is a rising global healthcare concern that needs urgent attention as growing number of infections become difficult to treat with the currently available antibiotics. This is particularly true for mycobacterial infections like tuberculosis and leprosy and those with emerging opportunistic pathogens such as Mycobacterium abscessus , where multi-drug resistance leads to increased healthcare cost and mortality. M. abscessus is a highly drug-resistant non-tuberculous mycobacterium which causes life-threatening infections in people with chronic lung conditions such as cystic fibrosis. In this study, we explore M. abscessus phosphopantetheine adenylyl transferase (PPAT), an enzyme involved in the biosynthesis of Coenzyme A, as a target for the development of new antibiotics. We provide structural insights into substrate and feedback inhibitor binding modes of M. abscessus PPAT, thereby setting the basis for further chemical exploration of the enzyme. We then utilize a multi-dimensional fragment screening approach involving biophysical and structural analysis, followed by evaluation of compounds from a previous fragment-based drug discovery campaign against M. tuberculosis PPAT ortholog. This allowed the identification of an early-stage lead molecule exhibiting low micro molar affinity against M. abscessus PPAT (K d 3.2 ± 0.8 µM) and potential new ways to design inhibitors against this enzyme. The resulting crystal structures reveal striking conformational changes and closure of solvent channel of M. abscessus PPAT hexamer providing novel strategies of inhibition. The study thus validates the ligandability of M. abscessus PPAT as an antibiotic target and identifies crucial starting points for structure-guided drug discovery against this bacterium.


  • Organizational Affiliation

    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Phosphopantetheine adenylyltransferase
A, B, C
162Mycobacteroides abscessusMutation(s): 0 
Gene Names: coaDMAB_3259c
EC: 2.7.7.3
UniProt
Find proteins for B1MDL6 (Mycobacteroides abscessus (strain ATCC 19977 / DSM 44196 / CCUG 20993 / CIP 104536 / JCM 13569 / NCTC 13031 / TMC 1543 / L948))
Explore B1MDL6 
Go to UniProtKB:  B1MDL6
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupB1MDL6
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.49 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.206 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 76.053α = 90
b = 125.052β = 90
c = 119.088γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Wellcome TrustUnited Kingdom--

Revision History  (Full details and data files)

  • Version 1.0: 2022-06-29
    Type: Initial release
  • Version 1.1: 2024-01-31
    Changes: Data collection, Refinement description