1C2I

RECRUITING ZINC TO MEDIATE POTENT, SPECIFIC INHIBITION OF SERINE PROTEASES

Summary for 1C2I

• Entry DOI: 10.2210/pdb1c2i/pdb
• Related: 1C1N 1C1O 1C1P 1C1Q 1C1R 1C1S 1C1T 1C1U 1C1V 1C1W 1C2D 1C2E 1C2F 1C2G 1C2H 1C2J 1C2L 1C2M
• Descriptor: TRYPSIN, CALCIUM ION, CHLORIDE ION, ... (7 entities in total)
• Functional Keywords: zn(ii)-mediated serine protease inhibitors, ph dependence, zn(ii) affinity stucture-based drug design, serine protease/inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Bos taurus (cattle)
• Cellular location: Secreted, extracellular space: P00760
• Total number of polymer chains: 1
• Total formula weight: 24022.54

Authors

Katz, B.A.,Luong, C. (deposition date: 1999-07-21, release date: 2000-07-26, Last modification date: 2024-11-06)

Primary citation

Katz, B.A.,Clark, J.M.,Finer-Moore, J.S.,Jenkins, T.E.,Johnson, C.R.,Ross, M.J.,Luong, C.,Moore, W.R.,Stroud, R.M.
Design of potent selective zinc-mediated serine protease inhibitors.
Nature, 391:608-612, 1998

PubMed Abstract: Many serine proteases are targets for therapeutic intervention because they often play key roles in disease. Small molecule inhibitors of serine proteases with high affinity are especially interesting as they could be used as scaffolds from which to develop drugs selective for protease targets. One such inhibitor is bis(5-amidino-2-benzimidazolyl)methane (BABIM), standing out as the best inhibitor of trypsin (by a factor of over 100) in a series of over 60 relatively closely related analogues. By probing the structural basis of inhibition, we discovered, using crystallographic methods, a new mode of high-affinity binding in which a Zn2+ ion is tetrahedrally coordinated between two chelating nitrogens of BABIM and two active site residues, His57 and Ser 195. Zn2+, at subphysiological levels, enhances inhibition by over 10(3)-fold. The distinct Zn2+ coordination geometry implies a strong dependence of affinity on substituents. This unique structural paradigm has enabled development of potent, highly selective, Zn2+-dependent inhibitors of several therapeutically important serine proteases, using a physiologically ubiquitous metal ion.

PubMed: 9468142
DOI: 10.1038/35422

Experimental method

X-RAY DIFFRACTION (1.47 Å)