5SYE

Near-atomic resolution cryo-EM reconstruction of doubly bound Taxol- and peloruside-stabilized microtubule

Summary for 5SYE

• Entry DOI: 10.2210/pdb5sye/pdb
• Related: 5SYC 5SYF 5SYG
• EMDB information: 8320 8321 8322 8323
• Descriptor: Tubulin alpha chain, Tubulin beta chain, GUANOSINE-5'-TRIPHOSPHATE, ... (7 entities in total)
• Functional Keywords: taxol, peloruside, microtubule, structural protein
• Biological source: Sus scrofa (Pig); More
• Total number of polymer chains: 2
• Total formula weight: 98898.16

Authors

Kellogg, E.H.,Nogales, E. (deposition date: 2016-08-10, release date: 2017-02-01, Last modification date: 2024-03-06)

Primary citation

Kellogg, E.H.,Hejab, N.M.,Howes, S.,Northcote, P.,Miller, J.H.,Diaz, J.F.,Downing, K.H.,Nogales, E.
Insights into the Distinct Mechanisms of Action of Taxane and Non-Taxane Microtubule Stabilizers from Cryo-EM Structures.
J. Mol. Biol., 429:633-646, 2017

PubMed Abstract: A number of microtubule (MT)-stabilizing agents (MSAs) have demonstrated or predicted potential as anticancer agents, but a detailed structural basis for their mechanism of action is still lacking. We have obtained high-resolution (3.9-4.2Å) cryo-electron microscopy (cryo-EM) reconstructions of MTs stabilized by the taxane-site binders Taxol and zampanolide, and by peloruside, which targets a distinct, non-taxoid pocket on β-tubulin. We find that each molecule has unique distinct structural effects on the MT lattice structure. Peloruside acts primarily at lateral contacts and has an effect on the "seam" of heterologous interactions, enforcing a conformation more similar to that of homologous (i.e., non-seam) contacts by which it regularizes the MT lattice. In contrast, binding of either Taxol or zampanolide induces MT heterogeneity. In doubly bound MTs, peloruside overrides the heterogeneity induced by Taxol binding. Our structural analysis illustrates distinct mechanisms of these drugs for stabilizing the MT lattice and is of relevance to the possible use of combinations of MSAs to regulate MT activity and improve therapeutic potential.

PubMed: 28104363
DOI: 10.1016/j.jmb.2017.01.001

Experimental method

ELECTRON MICROSCOPY (3.5 Å)