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PDBsum entry 6ps1
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Membrane protein
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PDB id
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6ps1
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References listed in PDB file
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Key reference
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Title
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Toward g protein-Coupled receptor structure-Based drug design using X-Ray lasers.
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Authors
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A.Ishchenko,
B.Stauch,
G.W.Han,
A.Batyuk,
A.Shiriaeva,
C.Li,
N.Zatsepin,
U.Weierstall,
W.Liu,
E.Nango,
T.Nakane,
R.Tanaka,
K.Tono,
Y.Joti,
S.Iwata,
I.Moraes,
C.Gati,
V.Cherezov.
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Ref.
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IUCrJ, 2019,
6,
1106-1119.
[DOI no: ]
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PubMed id
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Abstract
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Rational structure-based drug design (SBDD) relies on the availability of a
large number of co-crystal structures to map the ligand-binding pocket of the
target protein and use this information for lead-compound optimization via an
iterative process. While SBDD has proven successful for many drug-discovery
projects, its application to G protein-coupled receptors (GPCRs) has been
limited owing to extreme difficulties with their crystallization. Here, a method
is presented for the rapid determination of multiple co-crystal structures for a
target GPCR in complex with various ligands, taking advantage of the serial
femtosecond crystallography approach, which obviates the need for large crystals
and requires only submilligram quantities of purified protein. The method was
applied to the human β2-adrenergic receptor, resulting in eight
room-temperature co-crystal structures with six different ligands, including
previously unreported structures with carvedilol and propranolol. The generality
of the proposed method was tested with three other receptors. This approach has
the potential to enable SBDD for GPCRs and other difficult-to-crystallize
membrane proteins.
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