Hot-Spot Residues to be Mutated Common in G Protein-Coupled
Receptors of Class A: Identification of Thermostabilizing Mutations
Followed by Determination of Three-Dimensional Structures for Two
Example Receptors
Posted on 2017-06-23 - 12:34
G protein-coupled receptors (GPCRs),
which are indispensable to
life and also implicated in a number of diseases, construct important
drug targets. For the efficient structure-guided drug design, however,
their structural stabilities must be enhanced. An amino-acid mutation
is known to possibly lead to the enhancement, but currently available
experimental and theoretical methods for identifying stabilizing mutations
suffer such drawbacks as the incapability of exploring the whole mutational
space with minor effort and the unambiguous physical origin of the
enhanced or lowered stability. In general, after the identification
is successfully made for a GPCR, the whole procedure must be followed
all over again for the identification for another GPCR. Here we report
a theoretical strategy by which many different GPCRs can be considered
at the same time. The strategy is illustrated for three GPCRs of Class
A in the inactive state. We argue that a mutation of the residue at
a position of NBW = 3.39 (NBW is the Ballesteros–Weinstein number), a hot-spot
residue, leads to substantially higher stability for significantly
many GPCRs of Class A in the inactive state. The most stabilizing
mutations of the residues with NBW = 3.39
are then identified for two of the three GPCRs, using the improved
version of our free-energy function. These identifications are experimentally
corroborated, which is followed by the determination of new three-dimensional
(3D) structures for the two GPCRs. We expect that on the basis of
the strategy, the 3D structures of many GPCRs of Class A can be solved
for the first time in succession.
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Yasuda, Satoshi; Kajiwara, Yuta; Toyoda, Yosuke; Morimoto, Kazushi; Suno, Ryoji; Iwata, So; et al. (2017). Hot-Spot Residues to be Mutated Common in G Protein-Coupled
Receptors of Class A: Identification of Thermostabilizing Mutations
Followed by Determination of Three-Dimensional Structures for Two
Example Receptors. ACS Publications. Collection. https://doi.org/10.1021/acs.jpcb.7b02997
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AUTHORS (9)
SY
Satoshi Yasuda
YK
Yuta Kajiwara
YT
Yosuke Toyoda
KM
Kazushi Morimoto
RS
Ryoji Suno
SI
So Iwata
TK
Takuya Kobayashi
TM
Takeshi Murata
MK
Masahiro Kinoshita