3P4T

Crystal structure of a putative acyl-CoA dehydrogenase from Mycobacterium smegmatis


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.185 
  • R-Value Work: 0.153 
  • R-Value Observed: 0.155 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Increasing the structural coverage of tuberculosis drug targets.

Baugh, L.Phan, I.Begley, D.W.Clifton, M.C.Armour, B.Dranow, D.M.Taylor, B.M.Muruthi, M.M.Abendroth, J.Fairman, J.W.Fox, D.Dieterich, S.H.Staker, B.L.Gardberg, A.S.Choi, R.Hewitt, S.N.Napuli, A.J.Myers, J.Barrett, L.K.Zhang, Y.Ferrell, M.Mundt, E.Thompkins, K.Tran, N.Lyons-Abbott, S.Abramov, A.Sekar, A.Serbzhinskiy, D.Lorimer, D.Buchko, G.W.Stacy, R.Stewart, L.J.Edwards, T.E.Van Voorhis, W.C.Myler, P.J.

(2015) Tuberculosis (Edinb) 95: 142-148

  • DOI: https://doi.org/10.1016/j.tube.2014.12.003
  • Primary Citation of Related Structures:  
    3GVC, 3GVG, 3GWC, 3H7F, 3H81, 3HE2, 3HWI, 3HWK, 3HZG, 3ICO, 3KHP, 3LLS, 3MOY, 3MPZ, 3MYB, 3NDN, 3NDO, 3NF4, 3NG3, 3NJD, 3NWO, 3O0M, 3O38, 3OC6, 3OC7, 3OI9, 3OKS, 3OME, 3P0T, 3P2Y, 3P4I, 3P4T, 3P5M, 3P85, 3PE8, 3PK0, 3PPI, 3PZY, 3Q1T, 3Q8N, 3QBP, 3QDF, 3QHA, 3QIV, 3QK8, 3QKA, 3QLJ, 3QMJ, 3QRE, 3QUA

  • PubMed Abstract: 

    High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus "homolog-rescue" strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. Of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.


  • Organizational Affiliation

    Seattle Structural Genomics Center for Infectious Disease, United States; Seattle Biomedical Research Institute, 307 Westlake Ave N, Suite 500, Seattle, WA 98109, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Putative acyl-CoA dehydrogenase
A, B
403Mycolicibacterium smegmatis MC2 155Mutation(s): 0 
Gene Names: MSMEG_5491
EC: 1.1.1.35
UniProt
Find proteins for A0R3J1 (Mycolicibacterium smegmatis (strain ATCC 700084 / mc(2)155))
Explore A0R3J1 
Go to UniProtKB:  A0R3J1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA0R3J1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FAO
Query on FAO

Download Ideal Coordinates CCD File 
D [auth A],
E [auth B]
[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl (2R,3S,4S)-5-[(4aS,10aR)-7,8-dimethyl-2,4-dioxo-1,3,4,4a,5,10a-hexahydrobenzo[g]pteridin-10(2H)-yl]-2,3,4-trihydroxypentyl dihydrogen diphosphate
C27 H37 N9 O15 P2
VSWYNLHGQAGAHX-AWYOOINRSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A],
F [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

Unit Cell:
Length ( Å )Angle ( ˚ )
a = 161.93α = 90
b = 64.75β = 112.04
c = 83.81γ = 90
Software Package:
Software NamePurpose
BOSdata collection
REFMACrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-10-20
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2015-04-22
    Changes: Database references
  • Version 1.3: 2017-11-08
    Changes: Refinement description
  • Version 1.4: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description