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'''Selective inhibition of trypsins by insect peptides: role of P6-P10 loop''' | '''Selective inhibition of trypsins by insect peptides: role of P6-P10 loop''' | ||
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==About this Structure== | ==About this Structure== | ||
Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1WO9 OCA]. | |||
==Reference== | ==Reference== | ||
Selective inhibition of trypsins by insect peptides: role of P6-P10 loop., Kellenberger C, Ferrat G, Leone P, Darbon H, Roussel A, Biochemistry. 2003 Nov 25;42(46):13605-12. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14622007 14622007] | Selective inhibition of trypsins by insect peptides: role of P6-P10 loop., Kellenberger C, Ferrat G, Leone P, Darbon H, Roussel A, Biochemistry. 2003 Nov 25;42(46):13605-12. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14622007 14622007] | ||
[[Category: Darbon, H.]] | [[Category: Darbon, H.]] | ||
[[Category: Ferrat, G.]] | [[Category: Ferrat, G.]] | ||
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[[Category: Leone, P.]] | [[Category: Leone, P.]] | ||
[[Category: Roussel, A.]] | [[Category: Roussel, A.]] | ||
[[Category: | [[Category: Hydrolase inhibitor]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 13:56:24 2008'' | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | |||
Revision as of 10:56, 3 May 2008
Selective inhibition of trypsins by insect peptides: role of P6-P10 loop
Overview
PMP-D2 and HI, two peptides from Locusta migratoria, were shown to belong to the family of tight-binding protease inhibitors. However, they interact weakly with bovine trypsin (K(i) around 100 nM) despite a trypsin-specific Arg at the primary specificity site P1. Here we demonstrate that they are potent inhibitors of midgut trypsins isolated from the same insect and of a fungal trypsin from Fusarium oxysporum (K(i) <or= 0.02 nM). Therefore, they display a selectivity not existing for the parent chymotrypsin inhibitor PMP-C. By NMR, we demonstrate that HI possesses a highly rigid structure similar to the crystal structure of a variant of PMP-D2 in complex with bovine alpha-chymotrypsin. The main difference with PMP-C is located in the region from residues 20 to 24 (positions P6-P10) that interacts with the loop containing Gly173 in chymotrypsin. The corresponding residue in mammalian trypsins is always a proline that may generate a steric clash with the inhibitor. The residues thought to confer selectivity were mutated with PMP-C as a model. The resulting analogue PMP-D2(K10W,P21A,W25A) loses some activity toward insect and fungal trypsins but is a more potent inhibitor of mammalian trypsins, corresponding to a decrease of selectivity. This work represents a first attempt in tuning the selectivity of natural peptidic serine protease inhibitors by mutating residues out of the reactive loop (P3-P'3).
About this Structure
Full crystallographic information is available from OCA.
Reference
Selective inhibition of trypsins by insect peptides: role of P6-P10 loop., Kellenberger C, Ferrat G, Leone P, Darbon H, Roussel A, Biochemistry. 2003 Nov 25;42(46):13605-12. PMID:14622007 Page seeded by OCA on Sat May 3 13:56:24 2008
