PDBsum entry 6mgo

Structural protein

PDB id: 6mgo

Contents

Protein chain

359 a.a.

Ligands

JQV

ADP

Metals

_CA

Waters ×113

PDB id:

6mgo

Name:

Structural protein

Title:

Structure of rabbit actin in complex with mycalolide b

Structure:

Actin, alpha skeletal muscle. Chain: a. Synonym: alpha-actin-1

Source:

Oryctolagus cuniculus. Rabbit. Organism_taxid: 9986. Organ: sceletal. Tissue: muscle

Resolution:

2.20Å R-factor: 0.164 R-free: 0.195

Authors:

J.S.Allingham,D.Trofimova

Key ref:

B.V.Pipaliya et al. (2021). Truncated Actin-Targeting Macrolide Derivative Blocks Cancer Cell Motility and Invasion of Extracellular Matrix. J Am Chem Soc, 143, 6847-6854. PubMed id: 33938740 DOI: 10.1021/jacs.0c12404

Date:

14-Sep-18 Release date: 21-Nov-18

Protein chain

P68135  (ACTS_RABIT) -  Actin, alpha skeletal muscle from Oryctolagus cuniculus

Seq: 377 a.a.

Struc: 359 a.a.

Enzyme reactions

• Enzyme class: E.C.3.6.4.- - ?????

DOI no: 10.1021/jacs.0c12404

J Am Chem Soc 143:6847-6854 (2021)

PubMed id: 33938740

Truncated Actin-Targeting Macrolide Derivative Blocks Cancer Cell Motility and Invasion of Extracellular Matrix.

B.V.Pipaliya, D.N.Trofimova, R.L.Grange, M.Aeluri, X.Deng, K.Shah, A.W.Craig, J.S.Allingham, P.A.Evans.

ABSTRACT

Cancer metastasis is a complex process involving highly motile tumor cells that breach tissue barriers, enter the bloodstream and lymphatic system, and disseminate throughout the body as circulating tumor cells. The primary cellular mechanism contributing to these critical events is the reorganization of the actin cytoskeleton. Mycalolide B (MycB) is an actin-targeting marine macrolide that can suppress proliferation, migration, and invasion of breast and ovarian cancer cells at low nanomolar doses. Through structure-activity relationship studies focused on the actin-binding tail region (C24-C35) of MycB, we identified a potent truncated derivative that inhibits polymerization of G-actin and severs F-actin by binding to actin's barbed end cleft. Biological analyses of this miniature MycB derivative demonstrate that it causes a rapid collapse of the actin cytoskeleton in ovarian cancer cells and impairs cancer cell motility and invasion of the extracellular matrix (ECM) by inhibiting invadopodia-mediated ECM degradation. These studies provide essential proof-of-principle for developing actin-targeting therapeutic agents to block cancer metastasis and establish a synthetically tractable barbed end-binding pharmacophore that can be further improved by adding targeting groups for precision drug design.