41HIGHLIGHTS 2020

The structural basis for cohesin-CTCF anchored loops, Y. Li (a), J.H. Haarhuis (b), Á. Sedeño Cacciatore (b), R. Oldenkamp (b), M.S. van Ruiten (b), L. Willems (b), H. Teunissen (b), K.W. Muir (a,c), E. de Wit (b), B.D. Rowland (b) and

D. Panne (a,d), Nature 578, 472-476 (2020); https://doi.org/10.1038/s41586- 019-1910-z. (a) European Molecular Biology Laboratory, Grenoble (France) (b) The Netherlands Cancer Institute,

Amsterdam (The Netherlands) (c) MRC Laboratory of Molecular Biology, Cambridge (UK) (d) Leicester Institute of Structural and Chemical Biology, University of Leicester (UK)

UNDERSTANDING BIASED SIGNALLING AT A G PROTEIN- COUPLED RECEPTOR

The structures of a G protein-coupled receptor coupled to either a G protein mimetic or arrestin have been determined, allowing the first detailed comparison between these complexes. This suggests new strategies that would allow the development of new drugs with reduced side effects through specifically targeting one complex rather than both.

PRINCIPAL PUBLICATION AND AUTHORS

vast majority of detectable loops are lost in a YxF mutant (Figures 26a,b). Quantifying the contact frequency of all the loops also showed a dramatic loss of these contacts (Figure 26c). Thus, the interaction captured in the SA2-SCC1- CTCF structure is required for formation of CTCF- anchored loops at TAD boundaries. A productive interaction between cohesin and CTCF can only form when cohesin approaches the N-terminal end of CTCF (Figure 26e). This feature likely explains why only pairs of convergently oriented CTCF sites allow formation of TADs.

Mutations found in cancer cluster in this CTCF/cohesin binding interface, suggesting that dysregulation of chromosome looping is causally related to disease. Bioinformatic analyses further indicate that similar YxF motifs are present in a number of known and potential novel cohesin regulators. These newly identified cohesin ligands are involved in a number of functionally divergent chromosomal processes, with the implication that chromosome looping by cohesin plays an important role in a number of fundamental genome transactions.

G protein-coupled receptors (GPCRs) are integral membrane proteins found at the surfaces of every cell in the human body. They are essential constituents of the molecular signalling system that choreographs the interplay between internal organs. There are about 800 different GPCRs encoded by the human genome and they are responsible for all aspects of physiology involving intercellular communication. The β1-adrenoceptor (β1AR) is an archetypal GPCR found in the heart, where it modulates heart function and is the site of action of beta blockers such as carvedilol that inhibit the receptor. The β2-receptor (β2AR) is a highly homologous receptor found in the lungs and is the site of action for asthma treatments, such as the drugs salbutamol and formoterol, that activate the receptor (agonists).

An ongoing quest for the pharmaceutical industry is to develop new drugs with reduced side effects, the latter being produced by many different mechanisms. One source of side effects

Fig. 27: The crystal structure of the formoterol-bound β1AR-Nb80 complex. a,b) Structural differences between the β1AR-arrestin complex (grey) and

the β1AR-Nb80 complex (rainbow). c,d) Comparison between the surfaces of β1AR-arrestin complex and the β2AR-G protein complex (3SN6).

The circle (magenta) shows different surfaces suitable for the development of biased drugs.