What started as the M.Sc. projects of Michaela Benová and Athanasios Tsiris, seeking potent and selective inhibition of #HDAC11, turned into a great collaboration between the labs of @christianaolsen.bsky.social and Christian Heinis led by @danieladankova.bsky.social.

Big congratulations, Daniela!

Thanks, Christian!

@naturecomms.bsky.social

Thank you as well to @snsf-ch.bsky.social and IRFD for funding my postdoc at EPFL, to the @swisschemistry.bsky.social foundation and La Caixa Foundation for supporting Polina and Esther, and other funding from @snsf-ch.bsky.social, EPFL and the Dubochet Center for Imaging.
(8/8)

This would not have been possible without the excellent (and very efficient!) contributions of Babatunde Ekundayo and Polina Foteva (who just defended her MSc thesis 🥳), of Dongchun Ni, Esther Calviño and Henning Stahlberg, or without the truly supportive guidance of @beatfierz.bsky.social.
(7/8)

The contacts of the catalytic domain with DNA, on the other hand, are responsible for maintaining #H3K36ac selectivity.
Mutating a key interacting loop helps release the enzyme from the nucleosome and become much more active on #H3K18ac substrates 🤯.
(6/8)

The multivalent interactions of the nucleosome-binding domain are important for both activities, especially to find #chromatin substrates in an environment full of nucleic acids.
Interestingly, this domain is only present in insects and most vertebrates.
(5/8)

By comparing structures trapped at each substrate position we could rationalize its activity and intrinsic selectivity 🔍.
#SIRT7 binding is optimal for targeting #H3K36ac, and it can only access #H3K18ac through partial disengagement from the nucleosome and DNA bending.
(4/8)

Babatunde Ekundayo generated beautiful high-resolution structures, where we identified:
- A unique N-terminal nucleosome-binding domain, which places the #SIRT7 catalytic domain by the H3 tail exit site
- Extensive contacts with the two DNA gyres!
(3/8)

We produced nucleosomes with a thiourea mechanism-based handle (MTU) at the H3K18 and H3K36 preferred substrate positions, through histone semi-synthesis and reconstitution in vitro.
This allowed us to stabilize specific enzyme:substrate complexes efficiently for #cryoEM.
(2/8)

Hi Dorien, I would love to be added to this started pack!