5xp3 | pdb_00005xp3
Crystal structure of apo T2R-TTL
Structural highlights
Function[TBA1B_PIG] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. [STMN4_RAT] Exhibits microtubule-destabilizing activity.[1] [2] [3] [F2Z5B2_PIG] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain.[RuleBase:RU003505] Publication Abstract from PubMedInhibitors that bind to the paclitaxel- or vinblastine-binding sites of tubulin have been part of the pharmacopoeia of anticancer therapy for decades. However, tubulin inhibitors that bind to the colchicine-binding site are not used in clinical cancer therapy, because of their low therapeutic index. To address multidrug resistance to many conventional tubulin-binding agents, numerous efforts have attempted to clinically develop inhibitors that bind the colchicine-binding site. Previously, we have found that millepachine (MIL), a natural chalcone-type small molecule extracted from the plant Millettia pachycarpa, and its two derivatives (MDs) SKLB028 and SKLB050 have potential antitumor activities both in vitro and in vivo. However, their cellular targets and mechanisms are unclear. Here, biochemical and cellular experiments revealed that the MDs directly and irreversibly bind beta-tubulin. X-ray crystallography of the tubulin-MD structures disclosed that the MDs bind at the tubulin intradimer interface and to the same site as colchicine and that their binding mode is similar to that of colchicine. Of note, MDs inhibited tubulin polymerization and caused G2/M cell cycle arrest. Comprehensive analysis further revealed that free MIL exhibits an s-cis conformation, whereas MIL in the colchicine-binding site in tubulin adopts an s-trans conformation. Moreover, introducing an alpha-methyl to MDs in order to increase the proportion of s-trans conformations augmented MDs' tubulin inhibition activity. Our study uncovers a new class of chalcone-type tubulin inhibitors that bind the colchicine-binding site in beta-tubulin and suggests that the s-trans conformation of these compounds may make them more active anticancer agents. The compound millepachine and its derivatives inhibit tubulin polymerization by irreversibly binding to the colchicine-binding site in beta-tubulin.,Jianhong Y, Wei Y, Yamei Y, Yuxi W, Tao Y, Linlin X, Xue Y, Caofeng L, Zuowei L, Xiaoxin C, Mengshi H, Li Z, Qiang Q, Heying P, Dan L, Fang W, Peng B, Jiaolin W, Haoyu Y Sr., Lijuan C J Biol Chem. 2018 Apr 24. pii: RA117.001658. doi: 10.1074/jbc.RA117.001658. PMID:29691282[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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