Structure of arylamine N-acetyltransferase from Mycobacterium tuberculosis determined by cross-seeding with the homologous protein from M. marinum: triumph over adversity

DOI: 10.1107/S0907444913015126
PMID: 23897467

Authors: Areej Abuhammad (University of Oxford) , Ed Lowe (University of Oxford) , Michael Mcdonough (University of Oxford) , Patrick D. Shaw Stewart (Douglas Instruments) , Stefan A. Kolek (Douglas Instruments) , Edith Sim (University of Oxford) , Elspeth F. Garman (Oxford University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acta Crystallographica Section D Biological Crystallography , VOL 69 , PAGES 1433 - 1446

State: Published (Approved)
Published: August 2013

Abstract: Arylamine N-acetyltransferase from Mycobacterium tuberculosis (TBNAT) plays an important role in the intracellular survival of the microorganism inside macrophages. Medicinal chemistry efforts to optimize inhibitors of the TBNAT enzyme have been hampered by the lack of a three-dimensional structure of the enzyme. In this paper, the first structure of TBNAT, determined using a lone crystal produced using cross-seeding with the homologous protein from M. marinum, is reported. Despite the similarity between the two enzymes (74% sequence identity), they show distinct physical and biochemical characteristics. The structure elegantly reveals the characteristic features of the protein surface as well as details of the active site of TBNAT relevant to drug-discovery efforts. The crystallographic analysis of the diffraction data presented many challenges, since the crystal was twinned and the habit possessed pseudo-translational symmetry.

Journal Keywords: tuberculosis; drug targets; cholesterol catabolism; arylamine N-acetyltransferase; microseed matrix screen; crystal microseeding; cross-seeding; twinning; pseudo-translational symmetry

Diamond Keywords: Tuberculosis (TB); Bacteria

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 07/08/2013 10:19

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)