7z3q

Crystal structure of the human leptin:LepR-CRH2 encounter complex to 3.6 A resolution.

spinqualitylabelsall models 7z3q, resolution 3.62Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7z3q is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.617Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease LEPR_HUMAN Obesity due to leptin receptor gene deficiency. The disease is caused by mutations affecting the gene represented in this entry. Function LEPR_HUMAN Receptor for obesity factor (leptin). On ligand binding, mediates signaling through JAK2/STAT3. Involved in the regulation of fat metabolism and, in a hematopoietic pathway, required for normal lymphopoiesis. May play a role in reproduction. Can also mediate the ERK/FOS signaling pathway (By similarity). Publication Abstract from PubMed 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. Mechanism of receptor assembly via the pleiotropic adipokine Leptin.,Tsirigotaki A, Dansercoer A, Verschueren KHG, Markovic I, Pollmann C, Hafer M, Felix J, Birck C, Van Putte W, Catteeuw D, Tavernier J, Fernando Bazan J, Piehler J, Savvides SN, Verstraete K Nat Struct Mol Biol. 2023 Apr;30(4):551-563. doi: 10.1038/s41594-023-00941-9. , Epub 2023 Mar 23. PMID:36959263 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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