Nanobody-enabled Structural Biology
Published work of the Steyaert lab (see www.steyaertlab.eu
for all details) established that the antigen binding fragments of Camelid heavy chain only antibodies - known as Nanobodies (Nbs)- constitute unique research tools in structural biology. By rigidifying flexible regions and obscuring aggregative surfaces, Nanobody complexes warrant conformationally uniform samples that are key to protein structure determination by X-ray crystallography or cryo-EM. We make and use nanobodies to investigate enzymes, membrane proteins and protein complexes that are involved in signal transduction. We focus on conformationally complex systems that have been resistant to structural investigation by conventional methods.Locking GPCR conformational states.
The active-state conformations of G Protein Coupled Receptors (GPCRs) are unstable in the absence of specific cytosolic signaling partners representing key challenges for structural biology. We developed conformational Nanobodies against the β2 adrenergic receptor, the muscarinic acetylcholine receptor and the μ-opoid receptor that exhibit G protein-like behavior, and obtained the first agonist-bound, active-state crystal structures of these receptor●Nb complexes. Stabilizing transient signaling complexes.
We developed nanobodies that stabilize the β2AR●Gs complex and others that bind to Vps34 complex II. These antibodies were instrumental for obtaining crystal structures of these key transient multiprotein assemblies, providing the first structural view on GPCR transmembrane signaling and on the regulation of autophagy, respectively. Unveiling conformational states of membrane transporters and ion channels.
Functional understanding of membrane transporters and ion channels requires the structural characterization of different conformational states. Our lab produces Nanobodies to lock and solve the structures of key functional conformations of several transporters and ion channels by X-ray crystallography. Investigating the mechanism and regulation of complex GTPases.
Guanine nucleotide binding proteins are regulatory hubs in nearly all cellular processes. While the small GTPases of the Ras superfamily have been relatively well characterized, the mechanism of complex multi-domain GTPases is much less established. The Versées lab studies the mechanism and regulation of particular complex GTPases that are implicated in bacterial virulence and persistence or have been linked to Parkinson disease and epilepsy.Founding ConFoTherapeutics.
We transferred know-how and IP to ConFo Therapeutics, a new spin off company that exploits the conformational complexity of therapeutic targets for better drug discovery.
26/09/2016 - Increasing the concentration of specific fats in the brain could suppress epileptic seizures. This is evident from ground-breaking research carried out by groups of Patrik Verstreken (VIB-KU Leuven) and Wim Versées (VIB-Vrije Universiteit Brussel).
24/06/2015 - The establishment of Confo Therapeutics, a spin-off of VIB and Vrije Universiteit Brussel, was announced today. A consortium led by Capricorn Health-Tech Fund with the participation of Qbic and SOFI.
18/12/2014 - Brian Kobilka shared the 2012 Nobel Prize in Chemistry with Robert Lefkowitz. A couple of months ago Kobilka was in Brussels to give a talk about his work on invitation of Jan Steyaert (VIB/Vrije Universiteit brussel).
10/10/2012 - Jan Steyaert and his colleagues were involved in the groundbreaking work in which Brian Kobilka’s research team discovered the structure of these receptors.
04/01/2012 - Great news to start 2012. Top journals Nature and Science are featuring research from VIB researchers at Vrije Universiteit Brussel in their 2011 highlights.
25/07/2011 - In a Nature article, an international consortium reveals the complete 3D structure of an activated GPCR (beta-2AR) in a complex with its G protein. The Jan Steyaert Lab (VIB-VUB) produced the Xaperone™ that holds these proteins together.
12/01/2011 - Using tiny antibodies, dubbed Xaperones (TM), scientists from VIB and Vrije Universiteit Brussels collaborated in elucidating the structure of the adrenaline receptor - a scientific first with possibly profound implications for drug development.