| First Author | Hamada K | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 18 | Pages | 4661-4666 |
| PubMed ID | 28416699 | Mgi Jnum | J:242232 |
| Mgi Id | MGI:5904707 | Doi | 10.1073/pnas.1701420114 |
| Citation | Hamada K, et al. (2017) IP3-mediated gating mechanism of the IP3 receptor revealed by mutagenesis and X-ray crystallography. Proc Natl Acad Sci U S A 114(18):4661-4666 |
| abstractText | The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is an IP3-gated ion channel that releases calcium ions (Ca2+) from the endoplasmic reticulum. The IP3-binding sites in the large cytosolic domain are distant from the Ca2+ conducting pore, and the allosteric mechanism of how IP3 opens the Ca2+ channel remains elusive. Here, we identify a long-range gating mechanism uncovered by channel mutagenesis and X-ray crystallography of the large cytosolic domain of mouse type 1 IP3R in the absence and presence of IP3 Analyses of two distinct space group crystals uncovered an IP3-dependent global translocation of the curvature alpha-helical domain interfacing with the cytosolic and channel domains. Mutagenesis of the IP3R channel revealed an essential role of a leaflet structure in the alpha-helical domain. These results suggest that the curvature alpha-helical domain relays IP3-controlled global conformational dynamics to the channel through the leaflet, conferring long-range allosteric coupling from IP3 binding to the Ca2+ channel. |
