Hot Topics in Contemporary Crystallography

 

by Croatian Association of Crystallographers

 

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       Šibenik, Croatia, May, 10th to 15th, 2014      

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Croatian Association of Crystallographers

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Bijenička c. 54

HR-10000 Zagreb

Croatia

 

 

Triumph over Adversity: the structure determination of TBNAT

Elspeth Garman, Department of Biochemistry, University of Oxford, Oxford, UK.

This talk will relate the history and outcome of a (very) challenging case for protein crystallography structure determination: that of Arylamine N-acetyltransferase from Mycobacterium tuberculosis (TBNAT). This enzyme 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. The structure of TBNAT was determined using a lone 25 micron crystal produced using cross seeding with the homologous protein (MMNAT) from M. marinum, following extensive difficulties which had to be overcome during expression,  purification and crystallisation of the enzyme. Despite the similarity between MMNAT and TBNAT (74% sequence identity), the enzymes show distinct physical and biochemical characteristics. The TBNAT structure [1] 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: these will be described.

[1] Areej Abuhammad, Edward D. Lowe, Michael A. McDonough, Patrick D. Shaw Stewart, Stefan A. Kolek, Edith Sim and Elspeth F. Garman. Acta Cryst. (2013). D69, 1433–1446

The workshop is generously supported by:


Ministry of Science, Education and Sports of the Republic of Croatia

International Union of Crystallography

European Crystallographic Association

www.rofa.at