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A Small Contribution to a Large System: The Leptin Receptor Complex. | LitMetric

AI Article Synopsis

  • * Understanding leptin signaling could lead to new treatments for obesity and its related diseases, but the exact structure of the leptin receptor complex is not well understood.
  • * This study explores the binding sites of leptin using engineered proteins and predictive modeling, revealing that one binding site plays a more complex role than previously thought, potentially involving another receptor for improved signaling.

Article Abstract

Obesity is a classified epidemic, increasing the risk of secondary diseases such as diabetes, inflammation, cardiovascular disease, and cancer. The pleiotropic hormone leptin is the proposed link for the gut-brain axis controlling nutritional status and energy expenditure. Research into leptin signaling provides great promise toward discovering therapeutics for obesity and its related diseases targeting leptin and its cognate leptin receptor (LEP-R). The molecular basis underlying the human leptin receptor complex assembly remains obscure, due to the lack of structural information regarding the biologically active complex. In this work, we investigate the proposed receptor binding sites in human leptin utilizing designed antagonist proteins combined with AlphaFold predictions. Our results show that binding site I has a more intricate role in the active signaling complex than previously described. We hypothesize that the hydrophobic patch in this region engages a third receptor forming a higher-order complex, or a new LEP-R binding site inducing allosteric rearrangement.

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Source
http://dx.doi.org/10.1021/acs.jpcb.3c01090DOI Listing

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