1QF0: THERMOLYSIN (E.C.3.4.24.27) COMPLEXED WITH (2-SULPHANYL-3-PHENYLPROPANOYL)-PHE-TYR. PARAMETERS FOR ZN-BIDENTATION OF MERCAPTOACYLDIPEPTIDES IN METALLOENDOPEPTIDASE

Citation:
Abstract
Three alpha-mercaptoacyldipeptides differing essentially in the size of their C-terminal residues have been crystallized in the thermolysin active site. A new mode of binding was observed for 3 [HS-CH(CH(2)Ph)CO-Phe-Tyr] and 4 [HS-CH((CH(2))(4)CH(3))CO-Phe-Ala], in which the mercaptoacyl moieties act as bidentates with Zn-S and Zn-O distances of 2.3 and 2.4 A, respectively, the side chains fitting the S(1), S(1)', and S(2)' pockets. Moreover, a distance of 3.1 A between the sulfur atom and the OE1 of Glu(143) suggests that they are H-bonded and that one of these atoms is protonated. This H-bond network involving Glu(143), the mercaptoacyl group of the inhibitor, and the Zn ion could be considered a "modified" transition state mimic of the peptide bond hydrolysis. Due to the presence of the hindering (5-phenyl)proline, the inhibitor HS-CH(CH(2)Ph)CO-Gly-(5-Ph)Pro (2) interacts through the usual Zn monodentation via the thiol group and occupancy of S(1)' and S(2)' subsites by the aromatic moieties, the proline ring being outside the active site. The inhibitory potencies are consistent with these structural data, with higher affinities for 3 (4.2 x 10(-)(8) M) and 4 (4.8 x 10(-)(8) M) than for 2 (1.2 x 10(-)(6) M). The extension of the results, obtained with thermolysin being considered as the model of physiological zinc metallopeptidases, allows inhibitor-recognition modes for other peptidases, such as angiotensin converting enzyme and neutral endopeptidase, to be proposed and opens interesting possibilities for the design of new classes of inhibitors.
PDB ID: 1QF0Download
MMDB ID: 11714
PDB Deposition Date: 1999/4/6
Updated in MMDB: 2007/10
Experimental Method:
x-ray diffraction
Resolution: 2.2  Å
Source Organism:
Similar Structures:
Biological Unit for 1QF0: monomeric; determined by author
Molecular Components in 1QF0
Label Count Molecule
Protein (1 molecule)
1
Protein (Thermolysin)
Molecule annotation
Chemicals (8 molecules)
1
1
2
4
3
1
4
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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