8AV2
Crystal structure for the FnIII module of mouse LEP-R in complex with the anti-LEP-R nanobody VHH-4.80
Summary for 8AV2
| Entry DOI | 10.2210/pdb8av2/pdb |
| Related | 7Z3R |
| Descriptor | Leptin receptor, anti-mLEPR VHH 4-80, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total) |
| Functional Keywords | leptin, lep-r, obesity, metabolism, energy balance, cytokine |
| Biological source | Mus musculus (house mouse) More |
| Total number of polymer chains | 4 |
| Total formula weight | 78570.09 |
| Authors | Verstraete, K.,Savvides, S.N.,Verschueren, K.G.,Tsirigotaki, A. (deposition date: 2022-08-26, release date: 2023-04-05, Last modification date: 2024-10-23) |
| Primary citation | Tsirigotaki, A.,Dansercoer, A.,Verschueren, K.H.G.,Markovic, I.,Pollmann, C.,Hafer, M.,Felix, J.,Birck, C.,Van Putte, W.,Catteeuw, D.,Tavernier, J.,Fernando Bazan, J.,Piehler, J.,Savvides, S.N.,Verstraete, K. Mechanism of receptor assembly via the pleiotropic adipokine Leptin. Nat.Struct.Mol.Biol., 30:551-563, 2023 Cited by PubMed Abstract: The adipokine Leptin activates its receptor LEP-R in the hypothalamus to regulate body weight and exerts additional pleiotropic functions in immunity, fertility and cancer. However, the structure and mechanism of Leptin-mediated LEP-R assemblies has remained unclear. Intriguingly, the signaling-competent isoform of LEP-R is only lowly abundant amid several inactive short LEP-R isoforms contributing to a mechanistic conundrum. Here we show by X-ray crystallography and cryo-EM that, in contrast to long-standing paradigms, Leptin induces type I cytokine receptor assemblies featuring 3:3 stoichiometry and demonstrate such Leptin-induced trimerization of LEP-R on living cells via single-molecule microscopy. In mediating these assemblies, Leptin undergoes drastic restructuring that activates its site III for binding to the Ig domain of an adjacent LEP-R. These interactions are abolished by mutations linked to obesity. Collectively, our study provides the structural and mechanistic framework for how evolutionarily conserved Leptin:LEP-R assemblies with 3:3 stoichiometry can engage distinct LEP-R isoforms to achieve signaling. PubMed: 36959263DOI: 10.1038/s41594-023-00941-9 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.75 Å) |
Structure validation
Download full validation report
