Direct targeting of Rab-GTPase-effector interactions.
Small GTPases are molecular switches using GDP/GTP alternation to control numerous vital cellular processes. Although aberrant function and regulation of GTPases are implicated in various human diseases, direct targeting of this class of proteins has proven difficult, as GTPase signaling and regulation is mediated by extensive and shallow protein interfaces. Here we report the development of inhibitors of protein-protein interactions involving Rab proteins, a subfamily of GTPases, which are key regulators of vesicular transport. Hydrocarbon-stapled peptides were designed based on crystal structures of Rab proteins bound to their interaction partners. These modified peptides exhibit significantly increased affinities and include a stapled peptide (StRIP3) that selectively binds to activated Rab8a and inhibits a Rab8a-effector interaction in vitro.
Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany); Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany).
Jochen
J
Spiegel
Philipp M
PM
Cromm
Aymelt
A
Itzen
Roger S
RS
Goody
Tom N
TN
Grossmann
Herbert
H
Waldmann
D000595:Amino Acid Sequence; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D060066:Protein Interaction Maps / Q000187:drug effects*; D020691:rab GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D010455:Peptides; C082377:RAB8A protein, human; D020691:rab GTP-Binding Proteins
Rab proteins; inhibitors; protein-protein interactions; stapled peptides