PDBsum entry 6f7c

Cell cycle

PDB id: 6f7c

Contents

Protein chains

431 a.a.

424 a.a.

118 a.a.

281 a.a.

Ligands

GTP ×2

GDP ×2

CVT

MES

ACP

Metals

_CA ×3

_MG ×5

Waters ×713

PDB id:

6f7c

Name:

Cell cycle

Title:

Tubulin-compound 12 complex

Structure:

Tubulin alpha-1b chain. Chain: a, c. Synonym: alpha-tubulin ubiquitous,tubulin k-alpha-1,tubulin alpha- ubiquitous chain. Tubulin beta-2b chain. Chain: b, d. Stathmin-4. Chain: e. Synonym: stathmin-like protein b3,rb3.

Source:

Bos taurus. Bovine. Organism_taxid: 9913. Organ: brain. Rattus norvegicus. Rat. Organism_taxid: 10116. Gene: stmn4. Expressed in: escherichia coli.

Resolution:

2.00Å R-factor: 0.213 R-free: 0.243

Authors:

T.Muehlethaler,A.E.Prota,M.O.Steinmetz

Key ref:

N.M.Cury et al. (2019). Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia. iScience, 21, 95. PubMed id: 31655259 DOI: 10.1016/j.isci.2019.10.003

Date:

08-Dec-17 Release date: 19-Dec-18

Protein chains

P81947  (TBA1B_BOVIN) -  Tubulin alpha-1B chain from Bos taurus

Seq: 451 a.a.

Struc: 431 a.a.

Protein chains

Q6B856  (TBB2B_BOVIN) -  Tubulin beta-2B chain from Bos taurus

Seq: 445 a.a.

Struc: 424 a.a.

Protein chain

P63043  (STMN4_RAT) -  Stathmin-4 from Rattus norvegicus

Seq: 189 a.a.

Struc: 118 a.a.

Protein chain

E1BQ43  (E1BQ43_CHICK) -

DOI no: 10.1016/j.isci.2019.10.003

iScience 21:95 (2019)

PubMed id: 31655259

Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia.

N.M.Cury, T.Mühlethaler, A.B.A.Laranjeira, R.R.Canevarolo, P.P.Zenatti, D.Lucena-Agell, I.Barasoain, C.Song, D.Sun, S.Dovat, R.A.Yunes, A.E.Prota, M.O.Steinmetz, J.F.Díaz, J.A.Yunes.

ABSTRACT

Tubulin is one of the best validated anti-cancer targets, but most anti-tubulin agents have unfavorable therapeutic indexes. Here, we characterized the tubulin-binding activity, the mechanism of action, and the in vivo anti-leukemia efficacy of three 3,4,5-trimethoxy-N-acylhydrazones. We show that all compounds target the colchicine-binding site of tubulin and that none is a substrate of ABC transporters. The crystal structure of the tubulin-bound N-(1'-naphthyl)-3,4,5-trimethoxybenzohydrazide (12) revealed steric hindrance on the T7 loop movement of β-tubulin, thereby rendering tubulin assembly incompetent. Using dose escalation and short-term repeated dose studies, we further report that this compound class is well tolerated to >100 mg/kg in mice. We finally observed that intraperitoneally administered compound 12 significantly prolonged the overall survival of mice transplanted with both sensitive and multidrug-resistant acute lymphoblastic leukemia (ALL) cells. Taken together, this work describes promising colchicine-site-targeting tubulin inhibitors featuring favorable therapeutic effects against ALL and multidrug-resistant cells.