Journal of Molecular Biology
Volume 366, Issue 2, 16 February 2007, Pages 375-381
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The Solution Structure of Antigen MPT64 from Mycobacterium tuberculosis Defines a New Family of Beta-Grasp Proteins

https://doi.org/10.1016/j.jmb.2006.11.039Get rights and content

Abstract

The MPT64 protein and its homologs form a highly conserved family of secreted proteins with unknown function that are found within the pathogenic Mycobacteria genus. The founding member of this family from Mycobacterium tuberculosis (MPT64 or protein Rv1980c) is expressed only when Mycobacteria cells are actively dividing. By virtue of this relatively unique expression profile, Rv1980c is currently under phase III clinical trials to evaluate its potential to replace tuberculin, or purified protein derivative, as the rapid diagnostic of choice for detection of active tuberculosis infection. We describe here the NMR solution structure of Rv1980c. This structure reveals a previously undescribed fold that is based upon a variation of a β-grasp motif most commonly found in protein–protein interaction domains. Examination of this structure in conjunction with multiple sequence alignments of MPT64 homologs identifies a candidate ligand-binding site, which may help guide future studies of Rv1980c function. The work presented here also suggests structure-based approaches for increasing the antigenic potency of a Rv1980c-based diagnostic.

Section snippets

Rv1980c adopts a novel fold containing a β-grasp motif

To provide unique and complementary insights into the potential functions of this protein family, we used heteronuclear NMR techniques to determine the solution structure of Rv1980c. A representation of the average Rv1980c structure along with overlaid stereo images of the 24 lowest energy backbone traces of Rv1980c are shown in Figure 1(a) and (b), respectively. In addition, structural statistics are summarized in Table 1. Details of NMR data collection and protein backbone and side-chain

Protein Data Bank accession codes

The coordinates for Rv1980c have been deposited under accession code 2HHI.

Acknowledgements

We thank Kasra Ramyar for helpful comments on the manuscript. This research was funded by grant AI69001 from the National Institute for Allergy and Infectious Diseases (to B.V.G. and J.H.L.).

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    Z.W. and B.M.P. contributed equally to this work.

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