Issue 2, 2013
From the journal:

Chemical Science

Mechanism of action of a Janus-faced single-domain proteininhibitor simultaneously targeting two peptidase classes†

Sergio Trillo-Muyo,a   Sergio Martínez-Rodríguez,b   Joan L. Arolas*a  and  F. Xavier Gomis-Rüth*a  

* Corresponding authors

a Proteolysis Lab, Molecular Biology Institute of Barcelona, Spanish Research Council CSIC, Barcelona Science Park; c/Baldiri Reixac, 15-21, 08028 Barcelona, Catalonia, Spain
E-mail: xgrcri@ibmb.csic.es, jlacri@ibmb.csic.es
Fax: +34 934034979
Tel: +34 934020186

b Department of Physical Chemistry, Biochemistry, and Inorganic Chemistry, University of Almería, 04210 Almería, Spain

Abstract

Protein inhibitors provide a physiological mechanism for the regulation of proteolytic enzymes. While most single-domain inhibitors have one reactive site with which they target peptidases of a specific catalytic class, selected specimens inhibit two peptidase molecules simultaneously, thus giving rise to ternary complexes. To study such inhibition, we analyzed the function of one of these proteins, sermetstatin, which strongly binds as a dimer to serine proteinases (SPs) and a metallopeptidase (MP). In addition, we determined the structures of the isolated inhibitor dimer and its heterotetrameric complexes with the SP subtilisin and the MP snapalysin, which reveal that inhibition occurs through two independent distal reactive sites. These structures and the derived model for the heterohexameric complex provide for the first time a detailed view of the molecular mechanism of simultaneous inhibition of proteinases belonging to two distinct mechanistic classes by a single-domain protein.

Graphical abstract: Mechanism of action of a Janus-faced single-domain protein inhibitor simultaneously targeting two peptidase classes

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Article information

DOI
https://doi.org/10.1039/C2SC21712K
Article type
Edge Article
Submitted
09 Oct 2012
Accepted
13 Nov 2012
First published
14 Nov 2012

Chem. Sci., 2013,4, 791-797

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Mechanism of action of a Janus-faced single-domain protein inhibitor simultaneously targeting two peptidase classes

S. Trillo-Muyo, S. Martínez-Rodríguez, J. L. Arolas and F. X. Gomis-Rüth, Chem. Sci., 2013, 4, 791 DOI: 10.1039/C2SC21712K

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