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affecting the wild-type gene in normal cells
Specifically, these inhibitors take advantage
of the oncogenic G12C mutation in K-Ras
and do not inhibit wild-type K-Ras in normal
cells. Such remarkable properties should
endow these inhibitors with a good therapeutic
window. Given that covalent K-Ras
inhibitors display specific activity in vivo
will be very exciting to see the progress of these
K-Ras inhibitors into clinical trials
Alexander V. Statsyuk
Department of Pharmacological and Pharmaceutical
Sciences, College of Pharmacy, University of Houston,
Houston, TX, USA.
Published online: 14 May 2018
1. Stephen, A. G., Esposito, D., Bagni, R. K. & McCormick, F.
Cancer Cell 25, 272–281 (2014).
2. Patricelli, M. P. et al. Cancer Discov. 6, 316–329 (2016).
3. Lito, P., Solomon, M., Li, L. S., Hansen, R. & Rosen, N. Science
351, 604–608 (2016).
4. Schindler, T. et al. Science 289, 1938–1942 (2000).
5. Hansen, R. et al. Nat. Struct. Mol. Biol. https://doi.org/10.1038/
6. Schwartz, P. A. et al. Proc. Natl Acad. Sci. USA 111, 173–178 (2014).
7. Doyle, A. G. & Jacobsen, E. N. Chem. Rev. 107, 5713–5743 (2007).
8. MacMillan, D. W. Nature 455, 304–308 (2008).
9. Kraut, J. Annu. Rev. Biochem. 46, 331–358 (1977).
10. Janes, M. R. et al. Cell 172, 578–589.e517 (2018).
11. Zeng, M. et al. Cell Chem. Biol. 24, 1005–1016.e1003 (2017).
12. Kawabata, T. & Go, N. Proteins 68, 516–529 (2007).
13. Backus, K. M. et al. Nature 534, 570–574 (2016).
14. Zhao, Q. et al. J. Am. Chem. Soc. 139, 680–685 (2017).
15. Hacker, S. M. et al. Nat. Chem. 9, 1181–1190 (2017).
16. Hanke, J. H. et al. J. Biol. Chem. 271, 695–701 (1996).
17. Bishop, A. C. et al. Nature 407, 395–401 (2000).
18. Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M.
Nature 503, 548–551 (2013).
19. Hunter, J. C. et al. Proc. Natl Acad. Sci. USA 111, 8895–8900 (2014).
The authors declare no competing interests.
NATURE STRUCTURAL & MOLECULAR BIOLOGY | VOL 25 | JUNE 2018 | 435–439 | www.nature.com/nsmb
© 2018 Nature America Inc., part of Springer Nature. All rights reserved.
Strength in numbers—an arrestin interaction code
Activation signals from GPCRs, the largest receptor family, are transmitted to heterotrimeric G proteins and
arrestins, and can be dierentially modulated by GPCR phosphorylation. In a recent article, available data, including
multiple arrestin structures, are analyzed to decipher common and state-speciﬁc conformational changes in
arrestins and how these depend on patterns of receptor phosphorylation.
Christopher J. Draper-Joyce and Arthur Christopoulos
-protein-coupled receptors (GPCRs)
are the largest family of receptors
encoded by the human genome
(> 800 members) and are major conduits
by which cells sense and respond to their
external environment upon activation by a
diverse array of stimuli, including photons,
ions, nutrients, lipids, hormones, large
proteins and even mechanical signals
Signal transfer by GPCRs is mediated by
two major families of transducer proteins,
heterotrimeric G proteins (comprising just
21 members) and arrestins (comprising just
4 members). Some of the major challenges in
modern life sciences are to understand how
so many diverse types of GPCR can display
extraordinary degrees of selectivity when
interacting with such a relatively limited
repertoire of transducer proteins; what are
the molecular determinants governing such
selectivity; and how these events can be
orchestrated to mediate cell fate decisions
in a cell-type-specific, location-specific
and temporal manner. In the current issue
of Nature Structural & Molecular Biology,
Sente et al.
address one key aspect of
these challenges by applying large-scale
bioinformatics using available structural
information to build a set of rules describing
conformational changes governing arrestin
function that can be transferred between
different arrestin conformations, explain
current known features of the GPCR-
arrestin interaction ‘life cycle’, and also
identify novel arrestin ‘micro-locks’ and
other unappreciated properties underlying
conformational rearrangements that occur
as arrestins interact with GPCRs.
The arrestin family consists of two
retinal isoforms, visual arrestin (arrestin 1)
and cone arrestin (arrestin 4), and two
nonvisual (far more ubiquitously expressed)
arrestins, β -arrestin-1 (arrestin 2)
and β -arrestin-2 (arrestin 3)
were originally identified as important
regulators in the desensitization and/or
internalization of GPCRs. The classical view
was that, upon agonist binding to GPCRs,
G-protein-coupled receptor kinases (GRKs)
phosphorylate active state GPCRs on serine
or threonine residues within the C-terminal
tail and intracellular loops of the receptor to
facilitate arrestin recruitment and thereby
terminate (‘arrest’) GPCR signaling via
steric hindrance of G protein effectors, as
well as facilitating interactions with key
components of the endocytic process to
sequester GPCRs within clathrin-coated
pits to be trafficked to endosomes
internalized, GPCRs can be targeted for
either degradation or recycling
prototypical function of arrestins as simple
GPCR signal terminators is outdated
Arrestins are now acknowledged to act
as multifunctional adaptor–transducer
proteins that regulate a vast array of cellular
functions, independently of their ability
to abrogate G-protein-mediated signaling
and contingent on their additional ability to
initiate novel waves of intracellular signaling
in a G-protein-independent manner
Indeed, there has been an increasing focus in
GPCR drug discovery on the identification
of ligands that selectively activate either
G-protein- or β -arrestin-mediated signaling
in an attempt to develop pathway-selective
(rather than receptor-selective) ligands to
allow separation of signaling mediating
beneficial effects from that resulting in
adverse effects, a phenomenon known as
. Most recently, GPCR–G
protein–arrestin super-complexes have
been identified, in which an arrestin is able
to concomitantly interact with a GPCR
and a G protein, depending on the relative
transducer conformations, to differentially
modulate GPCR endocytosis and ERK
. Clearly, these studies highlight
both the relevance and ongoing knowledge
gaps associated with understanding the
full repertoire of GPCR-transducer protein
interactions and their functional sequelae in
health and disease.
A key component to the multifunctional
properties of the GPCR-arrestin interaction
is the ability of arrestins to recognize
different phosphorylation patterns
(commonly termed the phosphorylation
barcode) of activated receptors
. A logical