1qf0
From Proteopedia
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'''THERMOLYSIN (E.C.3.4.24.27) COMPLEXED WITH (2-SULPHANYL-3-PHENYLPROPANOYL)-PHE-TYR. PARAMETERS FOR ZN-BIDENTATION OF MERCAPTOACYLDIPEPTIDES IN METALLOENDOPEPTIDASE''' | '''THERMOLYSIN (E.C.3.4.24.27) COMPLEXED WITH (2-SULPHANYL-3-PHENYLPROPANOYL)-PHE-TYR. PARAMETERS FOR ZN-BIDENTATION OF MERCAPTOACYLDIPEPTIDES IN METALLOENDOPEPTIDASE''' | ||
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[[Category: Tiraboschi, G.]] | [[Category: Tiraboschi, G.]] | ||
[[Category: Tomas, A.]] | [[Category: Tomas, A.]] | ||
| - | [[Category: | + | [[Category: Neutral endopeptidase]] |
| - | [[Category: | + | [[Category: Zn metallopeptidase]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 06:11:09 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 03:11, 3 May 2008
THERMOLYSIN (E.C.3.4.24.27) COMPLEXED WITH (2-SULPHANYL-3-PHENYLPROPANOYL)-PHE-TYR. PARAMETERS FOR ZN-BIDENTATION OF MERCAPTOACYLDIPEPTIDES IN METALLOENDOPEPTIDASE
Overview
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.
About this Structure
1QF0 is a Single protein structure of sequence from Bacillus thermoproteolyticus. Full crystallographic information is available from OCA.
Reference
Crystal structures of alpha-mercaptoacyldipeptides in the thermolysin active site: structural parameters for a Zn monodentation or bidentation in metalloendopeptidases., Gaucher JF, Selkti M, Tiraboschi G, Prange T, Roques BP, Tomas A, Fournie-Zaluski MC, Biochemistry. 1999 Sep 28;38(39):12569-76. PMID:10504225 Page seeded by OCA on Sat May 3 06:11:09 2008
