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Apo and InsP3-bound crystal structures of the ligand-binding domain of an InsP3 receptor

Abstract

We report the crystal structures of the ligand-binding domain (LBD) of a rat inositol 1,4,5-trisphosphate receptor (InsP3R) in its apo and InsP3-bound conformations. Comparison of these two conformations reveals that LBD's first β-trefoil fold (β-TF1) and armadillo repeat fold (ARF) move together as a unit relative to its second β-trefoil fold (β-TF2). Whereas apo LBD may spontaneously transition between gating conformations, InsP3 binding shifts this equilibrium toward the active state.

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Figure 1: Structures of LBD.
Figure 2: Structures and electron density maps of regions within LDB.
Figure 3: Comparison of InsP3-bound and InsP3-unbound LBD structures.

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Acknowledgements

We thank T.C. Südhof (Stanford University) for sharing the InsP3R1-cDNA, J.K. Foskett (University of Pennsylvania) for providing the InsP3R1-cDNA–containing plasmid and for discussion, K. Schmitz (University of Pennsylvania) for assistance in crystal diffraction, G. Van Duyne (University of Pennsylvania) for both the modified pET21 plasmid containing a TEV site and the TEV-cDNA–containing plasmid, staffs of the synchrotron beam lines at the Advanced Photon Source (GM/CA-CAT 23-ID-B and 23-ID-D) and the Advanced Light Source (8.2.1 and 8.2.2) for technical assistance, Y. Xu (University of Pennsylvania) for technical assistance, and P. De Weer (University of Pennsylvania) for critical review and discussion of our manuscript. This study was supported by the Howard Hughes Medical Institute.

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C.-C.L., K.B. and Z.L. conducted the experiments, analyzed the data and prepared the manuscript.

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Correspondence to Zhe Lu.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Table 1 and Supplementary Methods (PDF 14689 kb)

Supplementary Movie 1

LBD structures with and without InsP3 bound, viewed alternatingly as in Fig. 1a,b, then as in Fig. 1c,d, followed by a zoom-in view of the InsP3-binding region with InsP3-interacting side chains. β-TF2 was used as reference to align the bound and unbound structures. (MOV 2442 kb)

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Lin, CC., Baek, K. & Lu, Z. Apo and InsP3-bound crystal structures of the ligand-binding domain of an InsP3 receptor. Nat Struct Mol Biol 18, 1172–1174 (2011). https://doi.org/10.1038/nsmb.2112

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