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9puo

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Neutralizing monoclonal antibody Fab fragment bound to leptin

Structural highlights

9puo 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 3.1Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

LEP_HUMAN Defects in LEP may be a cause of obesity (OBESITY) [MIM: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.^[1]

Function

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.

Publication Abstract from PubMed

Leptin, a hormone primarily secreted by adipocytes, regulates energy balance and systemic metabolism through its interaction with the leptin receptor (LEPR). Beyond these functions, leptin signaling has been implicated in the pathogenesis of tissue fibrosis. Here, we report the x-ray crystal structures of a leptin-neutralizing antibody (hLep3) in the unbound and leptin-bound states. The interaction of this antibody with leptin mimics the interaction of the LEPR with leptin, providing direct insights into the mechanism by which the antibody disrupts leptin signaling. We furthermore evaluate the therapeutic potential of neutralizing leptin with this antibody across distinct mouse models of fibrosis affecting the kidney, liver, lung, heart, and blood vessels. Leptin neutralization markedly inhibited fibrosis progression in all models. Mechanistically, suppression of leptin activity reduces pro-inflammatory and profibrotic processes, underscoring its therapeutic potential. These findings suggest that leptin signaling plays a vital role in tissue fibrosis and that treatment with a leptin-neutralizing antibody may be a promising therapeutic approach.

Leptin as a key driver for organ fibrogenesis.,Sun XN, Chen S, Zhao S, Funcke JB, Virostek M, Pedersen L, Li C, Joung C, Lin Q, Li Y, Cobb A, Wang MY, Min K, Maya-Ramos L, Degasperi G, Liu J, Zhang N, An Z, Tomchick DR, Wynn RM, Oh DY, Scherer PE Sci Adv. 2025 Oct 24;11(43):eady7904. doi: 10.1126/sciadv.ady7904. Epub 2025 Oct , 22. PMID:41124259^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet. 1998 Mar;18(3):213-5. PMID:9500540 doi:10.1038/ng0398-213
↑ Sun XN, Chen S, Zhao S, Funcke JB, Virostek M, Pedersen L, Li C, Joung C, Lin Q, Li Y, Cobb A, Wang MY, Min K, Maya-Ramos L, Degasperi G, Liu J, Zhang N, An Z, Tomchick DR, Wynn RM, Oh DY, Scherer PE. Leptin as a key driver for organ fibrogenesis. Sci Adv. 2025 Oct 24;11(43):eady7904. PMID:41124259 doi:10.1126/sciadv.ady7904