7 Dec 2023

Celebrating 30 years of Structure

Journal Structure was launched in 1993 as the first journal exclusively dedicated to structural biology by our founding academic chief editors, Wayne A. Hendrickson and Carl-Ivar Br€ande´ n, who were later joined by Alan Fersht. Christopher Lima and Andrej Sali became academic chief editors of Structure in 2003, and they were at the helm of the journal for 18 years until stepping down in the autumn 2021.

Structure is now celebrating its 30th birthday with this special anniversary issue. Editors commissioned reviews to highlight recent developments in different areas of structural biology. Sabine Botha and Petra Fromme provide an overview of the current state of serial femtosecond crystallography (SFX) research, the impact COVID-19 had on the SFX community, and how scientists adapted to these challenges. Koji Yonekura and his co-workers describe their contributions toward the development of electron 3D crystallography/microcrystal electron diffraction (MicroED) and highlight applications and current limitations of this method. Vaibhav KumarShukla, Gabriella Heller, and Flemming Hansen discuss the impact of artificial intelligence (AI) on biomolecular nuclear magnetic resonance (NMR) spectroscopy. Tuo Wang and his colleagues report how solid-state NMR is used to study the structures of fungaland plant cell walls. Syma Khalid and her co-workers define the term ‘‘computational microbiology’’ and describe state-of-the-art molecular dynamics imulations of bacterial systems.

21 Nov 2023

Intrinsic structural dynamics dictate enzymatic activity and inhibition (PNAS)

Enzymes are known to sample various conformations, many of which are critical for their biological function. However, structural characterizations of enzymes predominantly focus on the most populated conformation. As a result, single-point mutations often produce structures that are similar or essentially identical to those of the wild-type enzyme despite large changes in enzymatic activity. Here, we show for mutants of a histone deacetylase enzyme (HDAC8) that reduced enzymatic activities, reduced inhibitor affinities, and reduced residence times are all captured by the rate constants between intrinsically sampled conformations that, in turn, can be obtained independently by solution NMR spectroscopy. Thus, for the HDAC8 enzyme, the dynamic sampling of conformations dictates both enzymatic activity and inhibitor potency. Our analysis also dissects the functional role of the conformations sampled, where specific conformations distinct from those in available structures are responsible for substrate and inhibitor binding, catalysis, and product dissociation. Precise structures alone often do not adequately explain the effect of missense mutations on enzymatic activity and drug potency. Our findings not only assign functional roles to several conformational states of HDAC8 but they also underscore the paramount role of dynamics, which will have general implications for characterizing missense mutations and designing inhibitors.

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