View source for 8av2


==Crystal structure for the FnIII module of mouse LEP-R in complex with the anti-LEP-R nanobody VHH-4.80==
<StructureSection load='8av2' size='340' side='right'caption='[[8av2]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8av2]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Lama_glama Lama glama] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8AV2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AV2 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.75&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8av2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8av2 OCA], [https://pdbe.org/8av2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8av2 RCSB], [https://www.ebi.ac.uk/pdbsum/8av2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8av2 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/LEPR_MOUSE LEPR_MOUSE] Receptor for hormone LEP/leptin (Probable) (PubMed:11861497). On ligand binding, mediates LEP central and peripheral effects through the activation of different signaling pathways such as JAK2/STAT3 and MAPK cascade/FOS (PubMed:10799542, PubMed:11861497, PubMed:11923481, PubMed:25383904). In the hypothalamus, LEP acts as an appetite-regulating factor that induces a decrease in food intake and an increase in energy consumption by inducing anorexinogenic factors and suppressing orexigenic neuropeptides, also regulates bone mass and secretion of hypothalamo-pituitary-adrenal hormones (PubMed:10660043, PubMed:12594516). In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic and affects innate and adaptive immunity (PubMed:11923481, PubMed:25383904). Control of energy homeostasis and melanocortin production (stimulation of POMC and full repression of AgRP transcription) is mediated by STAT3 signaling, whereas distinct signals regulate NPY and the control of fertility, growth and glucose homeostasis (PubMed:12594516). Involved in the regulation of counter-regulatory response to hypoglycemia by inhibiting neurons of the parabrachial nucleus (PubMed:25383904). Has a specific effect on T lymphocyte responses, differentially regulating the proliferation of naive and memory T-cells. Leptin increases Th1 and suppresses Th2 cytokine production (PubMed:9732873).<ref>PMID:10660043</ref> <ref>PMID:10799542</ref> <ref>PMID:11861497</ref> <ref>PMID:11923481</ref> <ref>PMID:12594516</ref> <ref>PMID:25383904</ref> <ref>PMID:9732873</ref> <ref>PMID:25232147</ref>   May transport LEP across the blood-brain barrier. Binds LEP and mediates LEP endocytosis (PubMed:17620316, PubMed:20223942). Does not induce phosphorylation of and activate STAT3 (PubMed:11923481, PubMed:20223942).<ref>PMID:11923481</ref> <ref>PMID:17620316</ref> <ref>PMID:20223942</ref>   Antagonizes Isoform A and isoform B-mediated LEP binding and endocytosis.<ref>PMID:17620316</ref> 
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== 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<ref>PMID:36959263</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Lama glama]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Savvides SN]]
[[Category: Tsirigotaki A]]
[[Category: Verschueren KG]]
[[Category: Verstraete K]]