PDBsum entry 5xp3

Structural protein

PDB id: 5xp3

Contents

Protein chains

437 a.a.

428 a.a.

121 a.a.

334 a.a.

Ligands

GTP ×3

GOL

GDP

MES

ACP

Metals

_CA ×2

_MG ×4

Waters ×304

PDB id:

5xp3

Name:

Structural protein

Title:

Crystal structure of apo t2r-ttl

Structure:

Tubulin alpha-1b chain. Chain: a, c. Synonym: alpha-tubulin ubiquitous,tubulin k-alpha-1,tubulin alpha- ubiquitous chain. Engineered: yes. Tubulin beta chain. Chain: b, d. Engineered: yes. Stathmin-4.

Source:

Sus scrofa. Pig. Organism_taxid: 9823. Gene: tuba1b. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: tubb2b. Rattus norvegicus. Rat.

Resolution:

2.30Å R-factor: 0.192 R-free: 0.240

Authors:

Y.Wang,J.Yang,T.Wang,L.Chen

Key ref:

J.Yang et al. (2018). The compound millepachine and its derivatives inhibit tubulin polymerization by irreversibly binding to the colchicine-binding site in β-tubulin. J Biol Chem, 293, 9461-9472. PubMed id: 29691282 DOI: 10.1074/jbc.RA117.001658

Date:

31-May-17 Release date: 25-Oct-17

Protein chains

Q2XVP4  (TBA1B_PIG) -  Tubulin alpha-1B chain from Sus scrofa

Seq: 451 a.a.

Struc: 437 a.a.

Protein chains

F2Z5B2  (F2Z5B2_PIG) -  Tubulin beta chain from Sus scrofa

Seq: 425 a.a.

Struc: 428 a.a.*

Protein chain

P63043  (STMN4_RAT) -  Stathmin-4 from Rattus norvegicus

Seq: 189 a.a.

Struc: 121 a.a.

Protein chain

	E1BQ43  (E1BQ43_CHICK) -
	* PDB and UniProt seqs differ at 11 residue positions (black crosses)

DOI no: 10.1074/jbc.RA117.001658

J Biol Chem 293:9461-9472 (2018)

PubMed id: 29691282

The compound millepachine and its derivatives inhibit tubulin polymerization by irreversibly binding to the colchicine-binding site in β-tubulin.

J.Yang, W.Yan, Y.Yu, Y.Wang, T.Yang, L.Xue, X.Yuan, C.Long, Z.Liu, X.Chen, M.Hu, L.Zheng, Q.Qiu, H.Pei, D.Li, F.Wang, P.Bai, J.Wen, H.Ye, L.Chen.

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 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 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 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 α-methyl to MDs 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 β-tubulin and suggests that the s-trans conformation of these compounds may make them more active anticancer agents.