Henning Stahlberg

Jan 19, 2025 | nature.com | Prakash Arullampalam |Christian Gerber |Sabrina Guichard |Daniela Ross-Kaschitza |Martin Lochner |Jean-Sébastien Rougier | +6 more

Transient receptor potential (TRP) melastatin 4 (TRPM4) protein is a calcium-activated monovalent cation channel associated with various genetic and cardiovascular disorders. The anthranilic acid derivative NBA is a potent and specific TRPM4 inhibitor, but its binding site in TRPM4 has been unknown, although this information is crucial for drug development targeting TRPM4. We determine three cryo-EM structures of full-length human TRPM4 embedded in native lipid nanodiscs without inhibitor, bound to NBA, and an anthranilic acid derivative, IBA. We found that the small molecules NBA and IBA were bound in a pocket formed between the S3, S4, and TRP helices and the S4-S5 linker of TRPM4. Our structural data and results from patch clamp experiments enable validation of a binding site for small molecule inhibitors, paving the way for further drug development targeting TRPM4. TRPM4 is an ion channel associated with various genetic and cardiovascular disorders. The authors utilized cryo-EM and patch clamp experiments to determine the binding sites of potent and specific TRPM4 inhibitors driving further drug development targeting TRPM4.

Oct 24, 2024 | nature.com | Henning Stahlberg

Cryo-electron microscopy with energy resolution, using the EELS-STEM method, allows researchers to identify the approximate locations of certain heavier atoms within single frozen, hydrated protein particles.

Feb 27, 2024 | nature.com | Jaroslaw Sedzicki |Dongchun Ni |Henning Stahlberg

AbstractThe synthesis of complex sugars is a key aspect of microbial biology. Cyclic β-1,2-glucan (CβG) is a circular polysaccharide critical for host interactions of many bacteria, including major pathogens of humans (Brucella) and plants (Agrobacterium). CβG is produced by the cyclic glucan synthase (Cgs), a multi-domain membrane protein. So far, its structure as well as the mechanism underlining the synthesis have not been clarified.

Feb 14, 2024 | nature.com | Dongchun Ni |Liwei Guo |Henning Stahlberg |Shuguang Yuan

AbstractThe application of computational biology in drug development for membrane protein targets has experienced a boost from recent developments in deep learning-driven structure prediction, increased speed and resolution of structure elucidation, machine learning structure-based design and the evaluation of big data.

Nov 9, 2023 | nature.com | Hongtao Liu |Rossitza N. Irobalieva |Julia Kowal |Dongchun Ni |Kamil Nosol |Henning Stahlberg | +2 more

AbstractBSEP (ABCB11) is an ATP-binding cassette transporter that is expressed in hepatocytes and extrudes bile salts into the canaliculi of the liver. BSEP dysfunction, caused by mutations or induced by drugs, is frequently associated with severe cholestatic liver disease. We report the cryo-EM structure of glibenclamide-bound human BSEP in nanodiscs, revealing the basis of small-molecule inhibition.