Identification of the RelA domain responsible for action of a new NF-kappaB inhibitor DHMEQ.
A new NF-kappaB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) has a potential to be applied to clinical medicine as an anti-cancer and anti-inflammatory agent. DHMEQ inhibits localization of NF-kappaB in the nucleus and the inhibitory effect by DHMEQ is more potent on p50/RelA than on p50 homodimer. However, a molecular target of DHMEQ is unknown. In this study, we identified residues CEGRSAGSI, which appear in RelA (amino acids 38-46), c-Rel (28-36), and RelB (144-152), but not in p50 and p52, as a target of DHMEQ. As a possible mechanism, we propose that DHMEQ accesses CEGRSAGSI domain recognizing RSAGSI structure and directly binds to cysteine. This target domain appears to be unique among mammalian proteins. The results obtained in this study may provide better understanding of the action of DHMEQ and a key for developing a new NF-kappaB inhibitor with more potent activity.
Watanabe
Mariko
M
Department of Hematology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan.
Nakashima
Makoto
M
Togano
Tomiteru
T
Higashihara
Masaaki
M
Watanabe
Toshiki
T
Umezawa
Kazuo
K
Horie
Ryouichi
R
D000595:Amino Acid Sequence; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D001549:Benzamides / Q000378:metabolism* / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D003512:Cyclohexanones / Q000378:metabolism* / Q000494:pharmacology; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D017434:Protein Structure, Tertiary / Q000235:genetics; D017384:Sequence Deletion; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D001549:Benzamides; D003512:Cyclohexanones; D051996:Transcription Factor RelA; C464444:dehydroxymethylepoxyquinomicin; D003545:Cysteine