Μελέτη του κύριου θύλακα ειδικότητας (S1) των αμινοπεπτιδασών που παράγουν αντιγονικά πεπτίδια

Postgraduate Thesis uoadl:1318751 458 Read counter

Unit:
Κατεύθυνση Βιοχημεία
Library of the School of Science
Deposit date:
2012-07-12
Year:
2012
Author:
Ζερβούδη Ευθαλία
Supervisors info:
Κ. Γαλανοπούλου, Αναπληρώτρια Καθηγήτρια, Τμήμα Χημείας, Πανεπιστήμιο Αθηνών, Ε. Στρατίκος, Ερευνητής Β’, Ε.ΚΕ.Φ.Ε «Δημόκριτος»
Original Title:
Μελέτη του κύριου θύλακα ειδικότητας (S1) των αμινοπεπτιδασών που παράγουν αντιγονικά πεπτίδια
Languages:
Greek
Summary:
ER aminopeptidase 1 (ERAP1), ER aminopeptidase 2 (ERAP2) and Insulin Regulated
aminopeptidase (IRAP) are three homologous enzymes that play critical roles in
the generation of antigenic peptides. These aminopeptidases excise amino acids
from N-terminally extended precursors of antigenic peptides in order to
generate the correct length epitopes for binding onto MHC class I molecules.
The specificity of these peptidases can affect antigenic peptide selection, but
it has not yet been investigated in detail. In the present study we utilized a
collection of 82 fluorogenic substrates to define a detailed selectivity
profile for each of the three enzymes and to probe structural and functional
features of the primary specificity pocket (S1). Molecular modeling of the
three S1 pockets reveals substrate-enzyme interactions that are critical
determinants for specificity. The substrate selectivity profiles suggest that
IRAP largely combines the S1 specificity of ERAP1 and ERAP2, consistent with
its proposed biological function. IRAP, however, does not achieve this dual
specificity by simply combining structural features of ERAP1 and 2 but rather
by a unique amino acid change at position 541.
Our results provide insights on antigenic peptide selection and may prove
valuable in designing selective inhibitors or activity markers for this class
of enzymes. To test this hypothesis and using a rational, structure-based
approach, we have developed and evaluated a series of aniline and pyridine
analogs as well as a series of phosphinic transition-state analogs as putative
inhibitors of this group of enzymes, focusing on optimizing the specificity of
the S1 and S1’ subsites. Our results suggest that phosphinic transition-state
analogs are more active inhibitors (with inhibition potency down to 1μΜ) than
aniline and pyridine analogs. Finally, we conclude that this group of
inhibitors may constitute a novel avenue for the pharmacological modulation of
the immune response with multiple therapeutic applications from the regulation
of autoimmunity to cancer immunotherapy.
Keywords:
Aminopeptidase, Antigen, Inhibitors, Peptides, Major Histocompatibility Molecules
Index:
Yes
Number of index pages:
127-128
Contains images:
Yes
Number of references:
119
Number of pages:
146
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