Science - USA (2021-07-16)

As part of a recent series of online workshops organized by Tsinghua University and

Science/AAAS, an international panel of experts discussed the interplay of molecular

shapes and improving treatments.

Although scientists now know that the interaction of a drug with its targets

is more complicated than the oft-cited îlock-and-keyî mechanism, molecular

structures still matter. The physical shapes of the drug and the target impact

the efficacy of a treatment. Even small shifts in features can change the drugís

ef ficac y.

On March 5, 2021, pharmaceutical scientist Xiangyu Liu of Tsinghua University

discussed the role of beta-adrenergic receptors (βARs) in different physiological

states, such as resting or stressed. In particular, he described the roles of the

hormones epinephrine and norepinephrine, which interact differently with the

binding pockets of the two forms of βARs. In this work, he showed that drugs can

be developed to bind just one of the βAR forms, despite the identical structures

of the binding pockets.

βARs are part of the large family of G proteinñcoupled receptors (GPCRs),

which biochemist Bryan Roth of the University of North Carolina School of

Medicine discussed in the next presentation. Humans have more than 800 GPCR

types. Roth described how the structures of these molecules can be studied with

crystallographic methods and cryo-electron microscopy (cryo-EM). He noted that

more knowledge about the structure and function of GPCRs will speed up the

process of drug development.

The focus moved to ion channels in two presentations on April 15, 2021.

First, Princeton University molecular biologist Nieng Yan talked about one of

neurobiologyís best-known channels: the voltage-gated sodium channel (Nav),

which plays a key role in the initiation and propagation of nerve action potentials.

Using cryo-EM, she and her colleagues achieved near atomic-scale resolution of

several Nav channel structures, including human ones. Those structures can serve

as templates when designing drugs for Nav-related diseases.

Pain researcher David Julius of the University of California, San Francisco

explained how natural products can be used to study ion channels related to

somatosensory pathways. For example, his group studies the transient receptor

potential (TRP) channels involved in detecting thermal stimuli, such as hot and

cold sensations triggered by capsaicin and menthol, respectively. Insights gained

from this research can be used to elucidate signal transduction mechanisms and

potential therapeutic targets.

The discussions turned to immune-system receptors in the presentations

given on May 14, 2021. Biochemist Hao Wu of Harvard Medical School described

inflammasomes, which participate in the immune systemís inflammatory

response. Specifically, these supramolecular complexes cause the release

of cytokines and even cell death. She talked about her groupís work on how

the enzyme dipeptidyl peptidase 9 regulates the NLRP1 inflammasome.

Inflammasomes play critical roles in the mechanisms of many diseases, including

C O V I D -19.

To complete this series on structural biology and drug design, K. Christopher

Garciaóan expert on receptor systems at Stanford University School of Medicineó

talked about the impact of soluble or membrane-bound ligands on cell-surface

receptors that control various immune responses. In particular, Garciaís lab

explores receptor systems , such as the complex formed by a T-cell receptor

and the major histocompatibility complex. By studying the structure of the

ligandñreceptor complexes, he and his colleagues are able to analyze signaling

mechanisms of the immune system and use that information to engineer new

therapeutics.

As these presentations demonstrated, immune-related interactions are

complex and multifaceted. Endogenous and exogenous molecules interact with

a myriad of biochemical features that affect the overall binding process and drug

efficacy. By learning more about their related structures, biotechnology and

pharmaceutical companies can develop novel ways to address specific diseases

and design much-needed therapeutics.

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TsinghuañScience Workshops: Structural Biology and Drug Design

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IMAGES PROVIDED BY TSINGHUA UNIVERSITY

Workshop speakers. Top row (L to R): Xiangyu Liu, Bryan L. Roth, and David Julius. Bottom row (L to R): Nieng Yan, K. Christopher Garcia, and Hao Wu.

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