Structure of a GPCR bound to an anti-tumor agent
Figure: Structure of smoothened
receptor, showing bound anti-tumor agent LY2940680.
Ray Stevens group (The Scripps Research Institute) and collaborators
Ray Stevens' group published a G protein-coupled (GPCR)
structure directly related to cancer. Smoothened receptor is a key signal
transducer of the hedgehog signaling pathway, which is involved in
maintenance of normal development in animals. However, abnormal hedgehog
signaling is the cause for many types of cancers, and inhibition of the
smoothened receptor is an effective strategy to shut down abnormal hedgehog
signaling in cancerous conditions. The structure of human smoothened
receptor bound to an anti-tumor agent LY2940680 was solved to a resolution of
2.5 Å using the minibeam at GM/CA@APS. The structure reveals that the
smoothened receptor antagonist binds in a cavity embedded within the 7TM
helical bundle. The detailed structure of this ligand binding site could
provide a framework for structure based design of anticancer drug targeting
the smoothened receptor. In addition, the solved structure of human
smoothened receptor is the first non-class A GPCR structure reported to date.
The smoothened receptor belongs to class F GPCRs, which share less than 10%
sequence similarity with class A GPCRs (also known as rhodopsin-like GPCRs).
Surprisingly, the transmembrane portion of the smoothened receptor is highly
similar to class A GPCRs, although many motifs conserved in class A GPCRs are
missing, highlighting the incredible use of 7TM fold for divergent functions.
Wang, C, Wu, H, Katritch, V, Han, GW, Huang, XP, Liu, W, Siu, FY, Roth, BL,
Cherezov, V, Stevens, RC. Structure of the human smoothened receptor bound to
an antitumour agent, Nature 497, 338-343 (2013).