5XP3

Crystal structure of apo T2R-TTL

Summary for 5XP3

• Entry DOI: 10.2210/pdb5xp3/pdb
• Descriptor: Tubulin alpha-1B chain, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• Functional Keywords: colchicine binding domain, tubulin inhibitor, tublin, structural protein
• Biological source: Sus scrofa (Pig); More
• Cellular location: Cytoplasm, cytoskeleton: Q2XVP4 F2Z5B2; Golgi apparatus : P63043
• Total number of polymer chains: 6
• Total formula weight: 264613.98

Authors

Wang, Y.,Yang, J.,Wang, T.,Chen, L. (deposition date: 2017-05-31, release date: 2017-10-25, Last modification date: 2024-03-27)

Primary citation

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.,Lijuan, C.
The compound millepachine and its derivatives inhibit tubulin polymerization by irreversibly binding to the colchicine-binding site in beta-tubulin.
J. Biol. Chem., 2018

PubMed Abstract: Inhibitors 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 , and its two derivatives (MDs) SKLB028 and SKLB050 have potential antitumor activities both and However, their cellular targets and mechanisms are unclear. Here, biochemical and cellular experiments revealed that the MDs directly and irreversibly bind β-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 G/M cell-cycle arrest. Comprehensive analysis further revealed that free MIL exhibits an s- conformation, whereas MIL in the colchicine-binding site in tubulin adopts an s- conformation. Moreover, introducing an α-methyl to MDs to increase the proportion of s- conformations augmented MDs' tubulin inhibition activity. Our study uncovers a new class of chalcone-type tubulin inhibitors that bind the colchicine-binding site in β-tubulin and suggests that the s- conformation of these compounds may make them more active anticancer agents.

PubMed: 29691282
DOI: 10.1074/jbc.RA117.001658

Experimental method

X-RAY DIFFRACTION (2.3 Å)