PDBsum entry 7daf

Cell cycle

PDB id: 7daf

Contents

Protein chains

442 a.a.

423 a.a.

123 a.a.

351 a.a.

Ligands

GTP ×2

GDP ×2

MES ×2

GZX

ACP

Metals

_CL

_MG ×6

_CA ×4

Waters ×655

PDB id:

7daf

Name:

Cell cycle

Title:

Ixa in complex with tubulin

Structure:

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

Source:

Sus scrofa. Pig. Organism_taxid: 9823. Mus musculus. Mouse. Organism_taxid: 10090. Gene: stmn4. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.40Å R-factor: 0.175 R-free: 0.222

Authors:

C.Wu,Y.Wang

Key ref:

Q.Xiao et al. (2021). High-resolution X-ray structure of three microtubule-stabilizing agents in complex with tubulin provide a rationale for drug design. Biochem Biophys Res Commun, 534, 330-336. PubMed id: 33272565 DOI: 10.1016/j.bbrc.2020.11.082

Date:

16-Oct-20 Release date: 24-Mar-21

Protein chains

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

Seq: 451 a.a.

Struc: 442 a.a.*

Protein chains

A0A287AGU7  (A0A287AGU7_PIG) -  Tubulin beta chain from Sus scrofa

Seq: 445 a.a.

Struc: 423 a.a.

Protein chain

P63042  (STMN4_MOUSE) -  Stathmin-4 from Mus musculus

Seq: 189 a.a.

Struc: 123 a.a.

Protein chain

	E1BQ43  (E1BQ43_CHICK) -
	* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1016/j.bbrc.2020.11.082

Biochem Biophys Res Commun 534:330-336 (2021)

PubMed id: 33272565

High-resolution X-ray structure of three microtubule-stabilizing agents in complex with tubulin provide a rationale for drug design.

Q.Xiao, T.Xue, W.Shuai, C.Wu, Z.Zhang, T.Zhang, S.Zeng, B.Sun, Y.Wang.

ABSTRACT

Microtubule is a key component of cytoskeleton and has been considered as an important target for the treatment of cancer. In particular, the tubulin taxane-site inhibitors such as taxol analogs and epothilones have achieved great success in clinical trials. However, the structural basis of many taxane-site inhibitors is still lacking in exploring their mechanism of action. We here reported crystal complex structures for three taxane-site inhibitors, Ixabepilone, Epothilone B, and Epothilone D, which were determined to 2.4 Å, 2.4 Å, and 2.85 Å, respectively. The crystal structures revealed that these taxane-site inhibitors possess similar binding modes to that of Epothilone A at the taxane site, e.g. making critical hydrogen-bonding interactions with multiple residues on the M-loop, which facilitating the tubulin polymerization. Furthermore, we summarized the binding modes of almost all taxane-site inhibitors and identified novel taxane-site ligands with simpler chemical structures through virtual screening. On this basis, new derivatives with higher binding affinity to tubulin were designed and developed, which can form additional hydrogen bond interactions with tubulin. Overall, this work determined the mechanism of action of epothilones and provided a structural basis to design reasonably novel taxane-site inhibitors with simpler structure and improved pharmacokinetic properties.