1017233-79-2Relevant academic research and scientific papers
A natural-product switch for a dynamic protein interface
Scheepstra, Marcel,Nieto, Lidia,Hirsch, Anna K.H.,Fuchs, Sascha,Leysen, Seppe,Lam, Chan Vinh,In Het Panhuis, Leslie,Van Boeckel, Constant A.A.,Wienk, Hans,Boelens, Rolf,Ottmann, Christian,Milroy, Lech-Gustav,Brunsveld, Luc
, p. 6443 - 6448 (2014/06/24)
Small ligands are a powerful way to control the function of protein complexes via dynamic binding interfaces. The classic example is found in gene transcription where small ligands regulate nuclear receptor binding to coactivator proteins via the dynamic activation function 2 (AF2) interface. Current ligands target the ligand-binding pocket side of the AF2. Few ligands are known, which selectively target the coactivator side of the AF2, or which can be selectively switched from one side of the interface to the other. We use NMR spectroscopy and modeling to identify a natural product, which targets the retinoid X receptor (RXR) at both sides of the AF2. We then use chemical synthesis, cellular screening and X-ray co-crystallography to split this dual activity, leading to a potent and molecularly efficient RXR agonist, and a first-of-kind inhibitor selective for the RXR/coactivator interaction. Our findings justify future exploration of natural products at dynamic protein interfaces.
Structure-based optimization of cephalothin-analogue boronic acids as β-lactamase inhibitors
Morandi, Stefania,Morandi, Federica,Caselli, Emilia,Shoichet, Brian K.,Prati, Fabio
, p. 1195 - 1205 (2008/09/19)
Boronic acids have proved to be promising selective inhibitors of β-lactamases, acting as transition state analogues. Starting from a previously described nanomolar inhibitor of AmpC β-lactamase, three new inhibitors were designed to gain interactions with highly conserved residues, such as Asn343, and to bind more tightly to the enzyme. Among these, one was obtained by stereoselective synthesis and succeeded in placing its anionic group into the carboxylate binding site of the enzyme, as revealed by X-ray crystallography of the complex inhibitor/AmpC. Nevertheless, it failed at improving affinity, when compared to the lead from which it was derived. The origins of this structural and energetic discrepancy are discussed.
