News
Stereoselectivity and functional plasticity of a common ligand-binding pocket in TRPM3 out at Nature communications
Using cryo‑EM and electrophysiology, we, together with colleagues, unexpectedly find that chemically diverse plant‑derived and synthetic agonists and antagonists of TRPM3 act at the same binding pocket. We further show that mutations within this promiscuous site can alter stereoselectivity and, in some cases, reverse the functional effect of ligand binding, with important implications for TRPM3‑targeted drug discovery and therapy.
Palmitoylation-mediated regulation of KAT2A promotes lung metastasis in breast cancer is now out in Nature Cell Biology.
In this study we have supported the Fendt lab with biochemical analyses to complement insights obtained from cells and in vivo models.
MISO: Microfluidic protein isolation enables single particle cryo-EM structure determination from a single cell colony is published in Nature Methods
In this study a microfluidic device to isolate proteins from ultralow amounts for cryo-EM is described and named MISO. We have supported the Efremov lab with mammalian membrane proteins like murine TMEM16F and TMEM206 from cow, processed cryo-EM data and compared the MISO method with conventional purification and cryo-EM workflows.
Johanna receives an FWO Fellowship Fundamental Research. Congratulations Johanna! We are excited and thank FWO for the support.
Our preprint Stereoselectivity and functional plasticity of a common ligand-binding pocket in TRPM3 is published on bioRxiv
Using cryo-EM and electrophysiology we discover that chemically different plant-derived and synthetic antagonists and agonists of TRPM3 act on the same binding pocket. We report that mutations within this promiscuous ligand binding pocket, including novel gain-of-function patient mutations, can alter the stereoselectivity and, in some cases, invert the functional outcome of ligand binding, with important consequences for TRPM3-targeted drug discovery and therapy. We further describe in detail the binding geometry of primidone, an anticonvulsant and barbiturate congener, used in the treatment of epilepsy. This could serve as a starting point for the rational design of more potent drugs to modulate TRPM3.
Our paper Structures of native SV2A reveal the binding mode for tetanus neurotoxin and anti-epileptic racetams is out in Nature communications
In this study we provide evidence for SV2A as the protein-receptor for Tetanus Neurotoxin (TeNT) and deliver the structural basis for TeNT entry into central neurons. We unveil the precise geometry of TeNT binding to dipartite SV2-ganglioside receptors substantiating the dual-receptor hypothesis. Further, SV2A is the target for the major anti-seizure drug Levetiracetam for which we solved a drug-bound SV2A structure. This could lay the ground for the rational design of more potent medicine in the treatment of epilepsy.
The preprint MISO: Microfluidic protein isolation enables single particle cryo-EM structure determination from a single cell colony is published on bioRxiv
In this study a microfluidic device to isolate proteins from ultralow amounts for cryo-EM is described and named MISO. We have supported the Efremov lab with mammalian membrane proteins like murine TMEM16F and TMEM206 from cow, processed cryo-EM data and compared the MISO method with conventional purification and cryo-EM workflows.
Johanna secures a 1-year bridging scholarship from VUB. Congratulations!
Johanna Zipf joins the group as a PhD student
A summer school student joined our lab activities for four days and gave a helping hand
Hadrien successfully defended his Master thesis. Congratulations!
Alexander Shkumatov joins the group as an innovation scientist
Janine receives an FWO Junior Project Fundamental Research grant. We are excited and thankful to FWO for the support.
A summer school student joined our lab activities for four days and gave a helping hand
Cryo-EM structures of a LptDE transporter in complex with Pro-macrobodies offer insight into lipopolysaccharide translocation is out at Nature communications
This work provided the structural basis for LPS export to the outer bacterial membrane through visualization of the LptDE transporter ensemble in open and closed state by Cryo-EM. For this, Pro-macrobodies, rigid analogues of macrobodies and potent fiducial markers in cryo-EM, have been developed and applied in this study.
Hadrien Letourneur joined the lab as a master student
Our paper Structural basis for ion selectivity in TMEM175 K+ channels is published in eLife.
In this study we set out to provide first structural insight into a novel class of potassium channels on lysosomes. In combination with electrophysiology, high-resolution X-ray structures detailed how gating and potassium selectivity in the TMEM175 family is conferred through a hitherto unknown selectivity filter. High-resolution structures have been obtained through the development of a novel crystallization chaperone (macrobody) made of a nanobody fused to maltose binding protein (MBP).