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
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.
TsinghuañScience Workshops: Structural Biology and Drug Design
Produced by the Science
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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