The MRC DiMeN DTP welcomes applications from well-qualified international candidates, but the number of places for these students is extremely limited.

For questions not covered on the MRC DiMeN DTP web site or in the advert, please contact me by email through the link in the FindAPhD advert.

Applications need to be made to the MRC DiMeN DTP: www.dimen.org.uk. Applications by email cannot be considered.

While training in all aspects of the project will be provided, previous experience of synthetic chemistry research is desirable.

Powerful messages about the opportunity to learn much more about these channels by studying structural dependence on various factors such as temperature and membrane environment. Experimental structural biology is far from finished!

We thank our BBSRC @ukri.org, @thebhf.bsky.social, @wellcometrust.bsky.social, @royalsociety.org, @universityofleeds.bsky.social, and the Grant Agency of the Czech Republic for funding, and the incredible @astbury-bsl.bsky.social for facilities and support.

www.biorxiv.org/content/10.1...

This work was led by #cryoEM wizard Seb Porav, in a fantastic collaboration with Sasha Ptakova, @claudiabauer.bsky.social, @kasiahammond.bsky.social, David Beech, Viki Vlachova and @stemuench.bsky.social.

@astburycentre.bsky.social @bioscienceleeds.bsky.social @iphys-cas.bsky.social

In summary, we believe that this work represents a leap forward in understanding the #MolecularPharmacology of TRPC1/4/5 channels that will prove instrumental in TRPC1/4/5 drug discovery programmes.

In addition, our analyses allow us to rationalise the selectivity of EA with respect to related ion channels, as well as the pharmacological profile of TRPC1/4/5 inhibitors in ongoing clinical trials.

Structural similarity between TRPC1, TRPC4 and TRPC5, and the conservation of the EA binding site, suggest that our results extrapolate more generally to the TRPC1/4/5 sub-family – an emerging class of therapeutic targets for the treatment of anxiety disorders, cardiometabolic disease and pain.

We show that EA binds to a conserved lipid binding site between TRPC5 transmembrane domains and alters the aromatic interaction network of Phe520 with surrounding methionine residues. This work underscores the critical function of Met-aromatic motifs in ion channel #StructuralBiology and function.

We present nine new, high-resolution cryoEM structures of the human #TRPC5 #IonChannel in various states that reveal where and how EA binds to TRPC5 and - in combination with functional studies of TRPC5 variants - allow us to understand key molecular rearrangements related to channel gating.

#TRPchannels mediate cellular responses to various #NaturalProducts. #EnglerinA (EA), found in a plant used as a traditional medicine and a poison, is a potent and selective TRPC1/4/5 activator. However, how EA interacts with these channels has remained a mystery – until now.

"These look similar...let's mix them"

They probably cannot believe you would not want to be a most distinguished speaker at the 3rd Global Summit on Greater Hog Badger Genetics