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Conformational transitions for “activation” of Gαs proteins.

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posted on 2021-06-04, 18:27 authored by Jesse I. Mobbs, Matthew J. Belousoff, Kaleeckal G. Harikumar, Sarah J. Piper, Xiaomeng Xu, Sebastian G. B. Furness, Hari Venugopal, Arthur Christopoulos, Radostin Danev, Denise Wootten, David M. Thal, Laurence J. Miller, Patrick M. Sexton

The video displays the different transitions (morph between structures) that Gαs undergoes when moving from the inactive GDP-bound state (PDB: 6EG8) to the G0 state (guanine nucleotide free) induced by binding to selected activated class A or class B GPCRs. Transition 1: inactive to CCK1R-bound. Transition 2: inactive to β2-AR-bound. Transition 3: β2-AR-bound to CCK1R-bound. Transition 4: inactive to GLP-1R-bound to CCK1R-bound. Transition 5: inactive to EP4R-bound to CCK1R-bound. The protein backbone is displayed in ribbon format with the carboxyl-terminal residues of the αH5 shown also in stick format (coloured by heteroatom). Gs-GDP (grey; PDB: 6EG8), CCK1R-bound (gold), β2-AR-bound (blue; PDB: 3SN6), GLP-1R-bound (green; PDB:6X18), EP4R-bound (red; PDB: 7D7M). The αH5 has a “hook” conformation in the inactive G protein, and this conformation is maintained in most active state structures. In contrast, the far carboxyl-terminal residues of the αH5 unwinds to enable binding to the CCK1R. Unwinding of the α-5 helix is also seen with the EP4R complex, but this is accommodated by projection of the carboxyl-terminal amino acid side chains between the base of TM7 and TM1 (see Fig 4J). αH5, α5 helix; CCK, cholecystokinin; CCK1R, cholecystokinin type 1 receptor; GPCR, G protein–coupled receptor.