1Y3G: Crystal Structure Of A Silanediol Protease Inhibitor Bound To Thermolysin

Citation:
Abstract
Dialkylsilanediols have been found to be an effective functional group for the design of active-site-directed protease inhibitors, including aspartic (HIV protease) and metallo (ACE and thermolysin) proteases. The use of silanediols is predicated on its resemblance to the hydrated carbonyl transition-state structure of amide hydrolysis. This concept has been tested by replacing the presumed tetrahedral carbon of a thermolysin substrate with a silanediol group, resulting in an inhibitor with an inhibition constant K(i) = 40 nM. The structure of the silanediol bound to the active site of thermolysin was found to have a conformation very similar to that of a corresponding phosphonamidate inhibitor (K(i) = 10 nM). In both cases, a single oxygen is within bonding distance to the active-site zinc ion, mimicking the presumed tetrahedral transition state. There are binding differences that appear to be related to the presence or absence of protons on the oxygens attached to the silicon or phosphorus. This is the first crystal structure of an organosilane bound to the active site of a protease.
PDB ID: 1Y3GDownload
MMDB ID: 36938
PDB Deposition Date: 2004/11/24
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Similar Structures:
Biological Unit for 1Y3G: monomeric; determined by author and by software (PISA)
Molecular Components in 1Y3G
Label Count Molecule
Protein (1 molecule)
1
Thermolysin
Molecule annotation
Chemicals (10 molecules)
1
4
2
1
3
2
4
1
5
1
6
1
* Click molecule labels to explore molecular sequence information.

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