Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-49474
Ferraris, D M; Sbardella, D; Petrera, A; Marini, S; Amstutz, B; Coletta, M; Sander, P; Rizzi, M (2011). Crystal structure of mycobacterium tuberculosis ZMP1, a metalloprotease involved in pathogenicity. Journal of Biological Chemistry, 286(37):32475-32482.
Mycobacterium tuberculosis, the causative agent of tuberculosis, parasitizes host macrophages. The resistance of the tubercle bacilli to the macrophage hostile environment relates to their ability to impair phagosome maturation and its fusion with the lysosome, thus preventing the formation of the phago-lysosome and eventually arresting the process of phagocytosis. The M. tuberculosis zinc-dependent metalloprotease Zmp1 has been proposed to play a key role in the process of phagosome maturation inhibition and emerged as an important player in pathogenesis. Here we report the crystal structure of wild-type Zmp1 at 2.6 Å resolution in complex with the generic zinc-metalloprotease inhibitor Phosphoramidon, that we demonstrated to potently inhibit the enzyme. Our data represent the first structural characterization of a bacterial member of the zinc-dependent M13 endopeptidase family and revealed a significant degree of conservation with eukaryotic enzymes. However, structural comparison of the Zmp1-Phosphoramidon complex with homologous human proteins NEP and ECE-1 revealed unique features of the Zmp1 active site to be exploited for the rational design of specific inhibitors that may prove useful as a pharmacological tool for better understanding Zmp1 biological function.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Institute of Medical Microbiology|
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Deposited On:||14 Sep 2011 09:59|
|Last Modified:||29 Nov 2013 14:25|
|Publisher:||American Society for Biochemistry and Molecular Biology|
|Free access at:||Publisher DOI. An embargo period may apply.|
|Citations:||Web of Science®. Times Cited: 5|
Scopus®. Citation Count: 5
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