Structural biology: Mechanisms of novel anti-cancer drugs elucidated

Structural biology:  Mechanisms of novel anti-cancer drugs elucidated
Fig. 1: Cryo-EM structure and activity of dimeric human ATM. Credit: DOI: 10.1038/s41594-021-00654-x

Double-stranded breaks (DSBs) are among the most hazardous forms of DNA damage. The checkpoint protein kinase ATM plays a key role in the repair of DSBs. Many anti-tumor drugs act by inducing DSB formation, so inhibition of ATM should enhance the sensitivity of cancer cells to these agents.

Owing to its and conformational flexibility, ATM—like other members of the family of checkpoint kinases—has been inaccessible to high-resolution structural analysis. However, detailed structural information greatly facilitates for the development of targeted and selective anti-cancer agents.

With the aid of cryo-, Karl-Peter Hopfner's research group, in collaboration with the drug company Merck, has now elucidated the structure of ATM at a resolution that enables a virtually complete atomic model of the protein to be built. Moreover, the model allows the binding modes of novel ATM inhibitors that are currently in to be determined. The structural model can account for the selectivity of two ATM inhibitors, and thus provides the basis for the stereochemical optimization of new therapeutic compounds.

The study is published in Nature Structural & Molecular Biology.

More information: K. Stakyte et al, Molecular basis of human ATM kinase inhibition, Nature Structural & Molecular Biology (2021). DOI: 10.1038/s41594-021-00654-x

Citation: Structural biology: Mechanisms of novel anti-cancer drugs elucidated (2021, September 30) retrieved 4 December 2023 from
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.

Explore further

Opening the hatch to heal the break


Feedback to editors