Structurally distinct active conformations within a GPCR.
Robert Lefkowitz group (Duke University) and Andrew Kruse group (Harvard Medical School)
The groups of Robert Lefkowitz at Duke University and
Andrew Kruse at Harvard Medical School determined crystal structures of
the human angiotensin II type I receptor (AT1R), a G-protein coupled
receptor (GPCR) that controls cardiovascular and kidney function, in
complex with its endogenous activating hormone angiotensin II (AngII)
and two β-arrestin biased activators. When a GPCR is activated,
cellular signaling is propagated through both G-proteins and
β-arrestins. Some ligands preferentially or exclusively activate one
pathway, which is known as “biased signaling”. Since G-protein
signaling and β-arrestin signaling mediate distinct physiological
responses, GPCR drugs that promote biased signaling in many cases may
have superior therapeutic profiles (e.g., reducing on-target side
effects). In the AT1R G-protein signaling increases blood pressure,
whereas β-arrestin signaling promotes cardioprotective effects. The new
structures show that β-arrestin biased activators stabilize a
conformational state in the base of the ligand binding site and
receptor core that is distinctly different from that induced by AngII.
These results provide insight into the molecular basis for biased
signaling in GPCRs and may aid in the development of improved
therapeutics targeting these receptors.
Figure: Crystal structures of
the human angiotensin II receptor type 1 bound to the endogenous ligand
angiotensin II (green) and the biased agonist TRV026 (blue) are
overlaid, showing how the two ligands induce distinct structural
rearrangements in the receptor core.
Citation: Wingler, LM, Skiba, MA, McMahon, C, Staus,
DP, Kleinhenz ALW, Suomivuori, CM, Latorraca, NR, Dror, R,
Lefkowitz, RJ, Kruse, AC, Angiotensin and biased analogs
induce structurally distinct active conformations within a GPCR,
Science 367, 888-892 (2020). DOI: 10.1126/science.aay9813