View source for 8avf


==Human leptin in complex with the human LEP-R ectodomain fused to a C-terminal trimeric isoleucine GCN4 zipper (closed 3:3 model)==
<StructureSection load='8avf' size='340' side='right'caption='[[8avf]], [[Resolution|resolution]] 6.45&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8avf]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8AVF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AVF FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 6.45&#8491;</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=8avf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8avf OCA], [https://pdbe.org/8avf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8avf RCSB], [https://www.ebi.ac.uk/pdbsum/8avf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8avf ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/LEP_HUMAN LEP_HUMAN] Defects in LEP may be a cause of obesity (OBESITY) [MIM:[https://omim.org/entry/601665 601665]. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.<ref>PMID:9500540</ref> 
== Function ==
[https://www.uniprot.org/uniprot/LEP_HUMAN LEP_HUMAN] May function as part of a signaling pathway that acts to regulate the size of the body fat depot. An increase in the level of LEP may act directly or indirectly on the CNS to inhibit food intake and/or regulate energy expenditure as part of a homeostatic mechanism to maintain constancy of the adipose mass.
<div style="background-color:#fffaf0;">
== 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>
</div>
<div class="pdbe-citations 8avf" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Savvides SN]]
[[Category: Tsirigotaki A]]
[[Category: Verschueren KG]]
[[Category: Verstraete K]]