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Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4 Ghent University

Paul Collins, Michelle L. McCully, Laura Martinez-Munoz, Cesar Santiago, James Wheeldon, Stephan Caucheteux, Sylvia Thelen, Valentina Cecchinato, Julia M. Laufer, Vladimir Purvanov, et al.
The chemokine receptor, CXC chemokine receptor 4 (CXCR4), is selective for CXC chemokine ligand 12 (CXCL12), is broadly expressed in blood and tissue cells, and is essential during embryogenesis and hematopoiesis. CXCL14 is a homeostatic chemokine with unknown receptor selectivity and preferential expression in peripheral tissues. Here, we demonstrate that CXCL14 synergized with CXCL12 in the induction of chemokine responses in primary human ...

Substrate-dependent modulation of enzyme activity by allosteric effector antibodies Vrije Universiteit Brussel

John N Barlow, Katja Conrath, Jan Steyaert

We investigate the kinetic effects of antibody variable domain fragments derived from heavy chain antibodies (VHH domains) that behave as allosteric effectors of the nucleoside hydrolase from Trypanosoma vivax (TvNH). Strikingly, these antibodies can stimulate or inhibit TvNH steady-state activity, depending on the substrate used. This effect was investigated in greater detail using steady-state and pre-steady-state kinetic experiments. The ...

Structural basis for the allosteric modulation of rhodopsin by nanobody binding to its extracellular domain Vrije Universiteit Brussel Flanders Institute for Biotechnology

Arum Wu, David Salom, John D. Hong, Aleksander Tworak, Kohei Watanabe, Els Pardon, Jan Steyaert, Hideki Kandori, Kota Katayama, Philip D. Kiser, et al.

Rhodopsin is a prototypical G protein-coupled receptor (GPCR) critical for vertebrate vision. Research on GPCR signaling states has been facilitated using llama-derived nanobodies (Nbs), some of which bind to the intracellular surface to allosterically modulate the receptor. Extracellularly binding allosteric nanobodies have also been investigated, but the structural basis for their activity has not been resolved to date. Here, we report a ...

Allosteric modulation of a tyrosine kinase receptor by an extracellularly acting small-molecule chemical compound: inhibition of (lymph)angiogenesis in fish,frogs and mice by a multi-FGFR inhibitor KU Leuven

Frederik De Smet
De Receptor Tyrosine Kinase (RTK) superfamilie vormt een uiterst belangrijk doelwit in de huidige ontwikkeling van anti-angiogene/kanker geneesmiddelen. De huidige RTK inhibitoren binden aan en blokkeren de orthostere bindingsplaatsen van de endogene liganden of substraten van hun respectieve receptoren of enzymes. Allostere geneesmiddelen (of middelen die binden aan topografisch verschillende locaties) vormen een groep van veelbelovende ...

Selective Allosteric Modulation of N-Terminally Cleaved, but Not Full Length CCL3 in CCR1 KU Leuven

Olav Larsen
Chemokines undergo post-translational modification such as N-terminal truncations. Here, we describe how N-terminal truncation of full length CCL3(1-70) affects its activity at CCR1. Truncated CCL3(5-70) has 10-fold higher potency and enhanced efficacy in β-arrestin recruitment, but less than 2-fold increased potencies in G protein signaling determined by calcium release, cAMP and IP3 formation. Small positive ago-allosteric ligands modulate the ...

Therapeutic Potential of Allosteric Modulation of FGF Receptors KU Leuven

Frederik De Smet, Peter Carmeliet
Fibroblast Growth Factor receptors (FGFR) function as receptor tyrosine kinases (RTKs) and represent major targets for drug development. Traditional RTK inhibitors block orthosteric binding of ligands and substrates. Allosteric ligands provide a rich source of possible drug targets with clear therapeutic advantages, but the complexity of their mechanisms makes the discovery and development of allosteric drugs challenging. The FGFR has recently ...

Activation and allosteric modulation of a muscarinic acetylcholine receptor Vrije Universiteit Brussel

A. Kruse, Aaron Ring, Aashish Manglik, Els Pardon, Jan Steyaert, Jurgen Wess, Brian K Kobilka
Despite recent advances in crystallography and the availability of G-protein-coupled receptor (GPCR) structures, little is known about the mechanism of their activation process, as only the B2 adrenergic receptor (B2AR) and rhodopsin have been crystallized in fully active conformations. Here we report the structure of an agonist-bound, active state of the human M2 muscarinic acetylcholine receptor stabilized by a G-protein mimetic camelid ...

Allosteric Modulation of PS1/gamma-Secretase Conformation Correlates with Amyloid beta(42/40) Ratio KU Leuven

Kengo Uemura, Christina M Lill, Xuejing Li, Jessica A Peters, Alexander Ivanov, Zhanyun Fan, Bart De Strooper, Brian J Bacskai, Bradley T Hyman, Oksana Berezovska, et al.
BACKGROUND: Presenilin 1(PS1) is the catalytic subunit of gamma-secretase, the enzyme responsible for the Abeta C-terminal cleavage site, which results in the production of Abeta peptides of various lengths. Production of longer forms of the Abeta peptide occur in patients with autosomal dominant Alzheimer disease (AD) due to mutations in presenilin. Many modulators of gamma-secretase function have been described. We hypothesize that these ...

Modulation of the conformational state of the SV2A protein by an allosteric mechanism as evidenced by ligand binding assays KU Leuven

Veronique Daniëls
BACKGROUND AND PURPOSE: Synaptic vesicle protein 2A (SV2A) is the specific binding site of the anti-epileptic drug levetiracetam (LEV) and its higher affinity analogue UCB30889. Moreover, the protein has been well validated as a target for anticonvulsant therapy. Here, we report the identification of UCB1244283 acting as a SV2A positive allosteric modulator of UCB30889. EXPERIMENTAL APPROACH: UCB1244283 was characterized in vitro using ...