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Molecular mechanism of allosteric modulation: insight from a binding kinetics study at the human adenosine A1 receptor Vrije Universiteit Brussel

D. Deval, No name available, A. Massink, Van Velthoven Jpd, Georges Vauquelin, Ijzerman Ap, Heitman Lh
Background and purpose: Many G protein-coupled receptors (GPCRs) can be allosterically modulated by small molecule ligands. This modulation is best understood in terms of the kinetics of the ligand-receptor interaction. However, many current kinetic assays require at least the (radio-) labeling of the orthosteric ligand, which is impractical for studying a range of ligands. Here we describe the application of a so-called competition association ...

"Partial" competition of heterobivalent ligand binding may be mistaken for allosteric interactions: A comparison of different target interaction models Vrije Universiteit Brussel

Georges Vauquelin, David Hall, Steven Charlton
Background and Purpose: Non-competitive drugs that confer allosteric modulation of orthosteric ligand binding are of increasing interest as therapeutic agents. Sought-after advantages include a ceiling level to the drug effect and greater receptor subtype-selectivity. It is thus important to determine the mode of interaction of newly identified receptor ligands early in the drug discovery process and binding studies with labeled orthosteric ...

Inverted allosteric coupling between activation and inactivation gates in K+ channels Ghent University University of Antwerp

Alain Labro, D. Marien Cortes, Cholpon Tilegenova, Luis G. Cuello
The selectivity filter and the activation gate in potassium channels are functionally and structurally coupled. An allosteric coupling underlies C-type inactivation coupled to activation gating in this ion-channel family (i.e., opening of the activation gate triggers the collapse of the channel's selectivity filter). We have identified the second Threonine residue within the TTVGYGD signature sequence of K+ channels as a crucial residue for this ...

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 ...

Allosteric activation of ADAMTS13 by von Willebrand factor Ghent University KU Leuven

Joshua Muia, Jian Zhu, Garima Gupta, Sandra L Haberichter, Kenneth D Friedman, Hendrik Feys, Louis Deforche, Karen Vanhoorelbeke, Lisa A Westfield, Robyn Roth, et al.
The metalloprotease ADAMTS13 cleaves von Willebrand factor (VWF) within endovascular platelet aggregates, and ADAMTS13 deficiency causes fatal microvascular thrombosis. The proximal metalloprotease (M), disintegrin-like (D), thrombospondin-1 (T), Cys-rich (C), and spacer (S) domains of ADAMTS13 recognize a cryptic site in VWF that is exposed by tensile force. Another seven T and two complement C1r/C1s, sea urchin epidermal growth factor, and ...

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 ...

Involvement of the β3-α3 loop of the proline dehydrogenase domain in allosteric regulation of membrane association of proline utilization A Vrije Universiteit Brussel

Weidong Zhu, Ashley M Haile, Ranjan Kumar Singh, John D Larson, Danielle Smithen, Jie Y Chan, John J Tanner, Donald F Becker

Proline utilization A (PutA) from Escherichia coli is a membrane-associated trifunctional flavoenzyme that catalyzes the oxidation of proline to glutamate and moonlights as a transcriptional regulator. As a regulatory protein, PutA represses transcription of the put regulon, which contains the genes encoding PutA and the proline transporter PutP. The binding of proline to the proline dehydrogenase active site and the subsequent reduction of ...

Allosteric inhibition of VIM metallo-β-lactamases by a camelid nanobody Vrije Universiteit Brussel

Jean S Sohier, Clémentine Laurent, Andy Chevigné, Els Pardon, Vasundara Srinivasan, Ulrich Wernery, Patricia Lassaux, Jan Steyaert, Moreno Galleni

MβL (metallo-β-lactamase) enzymes are usually produced by multi-resistant Gram-negative bacterial strains and have spread worldwide. An approach on the basis of phage display was used to select single-domain antibody fragments (VHHs, also called nanobodies) that would inhibit the clinically relevant VIM (Verona integron-encoded MβL)-4 MβL. Out of more than 50 selected nanobodies, only the NbVIM_38 nanobody inhibited VIM-4. The paratope, ...

Radioligand dissociation measurements: potential interference of rebinding and allosteric mechanisms and physiological relevance of the biological model systems. Vrije Universiteit Brussel

Georges Vauquelin, Isabelle Van Liefde
Introduction
In many situations, optimal drug therapy requires continuing, high levels of target occupancy and this notion has led pharmacologists to focus attention to the rate by which drug candidates dissociate from their target. To this end, radioligand dissociation experiments are often carried out on in vitro models such intact cells and membranes thereof but the interpretation of the collected data is sometimes ambiguous.
Areas ...