Book of Abstracts: Albany 2011

category image Albany 2011
Conversation 17
June 14-18 2011
©Adenine Press (2010)

Structure-function Investigation of Metalloproteinases Provides Novel Insights into Drug Design

Matrix metalloproteinases (MMPs) and disintegrin metalloproteinases (ADAMs) are endopeptidases central to the degradation and remodeling of the extracellular matrix (ECM). These proteases also exhibit regulatory activity in cell signaling pathways and thus tissue homeostasis under normal conditions and in many diseases (1). Consequently, individual members of the MMP and ADAM protein families were identified as important therapeutic targets. However, designing effective inhibitors in vivo for this class of enzymes appears to be extremely challenging. This is attributed to the broad structural similarity of their active sites and apparently to the dynamic functional interconnectivity of MMPs with other proteases, their inhibitors, and substrates (the so-called degradome) in healthy and disease tissues, demonstrated to be detrimental to the therapeutic rationale (2-3). We present recent advancements in our understanding of MMPs structures, dynamics and their function as master regulators (4-7). We highlight the use of structural-kinetic experimental approach for protein-based drug design strategies, e.g. antibodies and protein scaffolds, targeting extracatalytic domains, which are central to proteolytic and non-proteolytic enzyme functions (3). Such rationally designed function blocking inhibitors may create new opportunities in disease management and in emerging therapies that require control of dysregulated MMP activity without causing severe side-effects.

  1. N. Sela-Passwell, G. Rosenblum, T. Shoham, I. Sagi, Biochim Biophys Acta. 1803, 29-38 (2010).
  2. I. Sagi M. Milla Anal. Biochem. 372, 1-10 (2008).
  3. N. Sela-Passwell, A. Trahtenhercts, A. Kr├╝ger, I. Sagi, Expert opinion on Drug Discovery In Press. (2011)
  4. A. Solomon, B. Akabayov, M. Milla, I. Sagi, PNAS U S A 104, 4931-4936 (2007).
  5. G. Rosenblum, P. Van den Steen, S.R. Cohen, G.J. Grossmann, A. Frenkel, R. Sertchook, N. Slack, R.W. Strange, G. Opdenakker, I. Sagi, Structure 10, 1227-36 (2007).
  6. G. Rosenblum, P. Van den Steen, S. Cohen, A.Bitler, A. D.D. Brand, G. Opdenakker, I. Sagi, PLos One 5 9-15 (2010).
  7. M. Grossman, D. Tworowski, M. Lee, Y. Levy, G. Murphy, I. Sagi, Biochemistry 49, 6184-6192. (2010).

Netta Sela-Passwell
Alla Trahtenhercts
and Irit Sagi

Department of Biological Regulation The Weizmann Institute of Science Rehovot, 76100, ISRAEL

Ph: (+9728) 934-2130
Fx: (+9728) 934-4136