1C1P: RECRUITING ZINC TO MEDIATE POTENT, SPECIFIC INHIBITION OF SERINE PROTEASES

Citation:
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.
PDB ID: 1C1PDownload
MMDB ID: 17460
PDB Deposition Date: 1999/7/21
Updated in MMDB: 2017/10
Experimental Method:
x-ray diffraction
Resolution: 1.37  Å
Source Organism:
Similar Structures:
Biological Unit for 1C1P: monomeric; determined by author
Molecular Components in 1C1P
Label Count Molecule
Protein (1 molecule)
1
Trypsin(Gene symbol: PRSS1)
Molecule annotation
Chemicals (6 molecules)
1
1
2
1
3
2
4
1
5
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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