3UTZ

Endogenous-like inhibitory antibodies targeting activated metalloproteinase motifs show therapeutic potential

Summary for 3UTZ

• Entry DOI: 10.2210/pdb3utz/pdb
• Descriptor: Metalloproteinase, light chain, Metalloproteinase, heavy chain, SULFATE ION, ... (4 entities in total)
• Functional Keywords: structural genomics, israel structural proteomics center, ispc, fab domain, immune system
• Biological source: Mus musculus (mouse); More
• Total number of polymer chains: 6
• Total formula weight: 145452.28

Authors

Sela-Passwell, N.,Kikkeri, R.,Dym, O.,Rozenberg, H.,Margalit, R.,Arad-Yellin, R.,Eisenstein, M.,Brenner, O.,Shoham, T.,Danon, T.,Shanzer, A.,Sagi, I.,Israel Structural Proteomics Center (ISPC) (deposition date: 2011-11-27, release date: 2011-12-14, Last modification date: 2024-10-30)

Primary citation

Sela-Passwell, N.,Kikkeri, R.,Dym, O.,Rozenberg, H.,Margalit, R.,Arad-Yellin, R.,Eisenstein, M.,Brenner, O.,Shoham, T.,Danon, T.,Shanzer, A.,Sagi, I.
Antibodies targeting the catalytic zinc complex of activated matrix metalloproteinases show therapeutic potential.
NAT.MED. (N.Y.), 18:143-147, 2012

PubMed Abstract: Endogenous tissue inhibitors of metalloproteinases (TIMPs) have key roles in regulating physiological and pathological cellular processes. Imitating the inhibitory molecular mechanisms of TIMPs while increasing selectivity has been a challenging but desired approach for antibody-based therapy. TIMPs use hybrid protein-protein interactions to form an energetic bond with the catalytic metal ion, as well as with enzyme surface residues. We used an innovative immunization strategy that exploits aspects of molecular mimicry to produce inhibitory antibodies that show TIMP-like binding mechanisms toward the activated forms of gelatinases (matrix metalloproteinases 2 and 9). Specifically, we immunized mice with a synthetic molecule that mimics the conserved structure of the metalloenzyme catalytic zinc-histidine complex residing within the enzyme active site. This immunization procedure yielded selective function-blocking monoclonal antibodies directed against the catalytic zinc-protein complex and enzyme surface conformational epitopes of endogenous gelatinases. The therapeutic potential of these antibodies has been demonstrated with relevant mouse models of inflammatory bowel disease. Here we propose a general experimental strategy for generating inhibitory antibodies that effectively target the in vivo activity of dysregulated metalloproteinases by mimicking the mechanism employed by TIMPs.

PubMed: 22198278
DOI: 10.1038/nm.2582

Experimental method

X-RAY DIFFRACTION (2.18 Å)