Peptide/Receptor Co-evolution Explains the Lipolytic Function of the Neuropeptide TLQP-21.

Clicks: 149
ID: 36147
2019
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Abstract
Structural and functional diversity of peptides and GPCR result from long evolutionary processes. Even small changes in sequence can alter receptor activation, affecting therapeutic efficacy. We conducted a structure-function relationship study on the neuropeptide TLQP-21, a promising target for obesity, and its complement 3a receptor (C3aR1). After having characterized the TLQP-21/C3aR1 lipolytic mechanism, a homology modeling and molecular dynamics simulation identified the TLQP-21 binding motif and C3aR1 binding site for the human (h) and mouse (m) molecules. mTLQP-21 showed enhanced binding affinity and potency for hC3aR1 compared with hTLQP-21. Consistently, mTLQP-21, but not hTLQP-21, potentiates lipolysis in human adipocytes. These findings led us to uncover five mutations in the C3aR1 binding pocket of the rodent Murinae subfamily that are causal for enhanced calculated affinity and measured potency of TLQP-21. Identifying functionally relevant peptide/receptor co-evolution mechanisms can facilitate the development of innovative pharmacotherapies for obesity and other diseases implicating GPCRs.
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sahu2019peptidereceptorcell Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Sahu, Bhavani S;Rodriguez, Pedro;Nguyen, Megin E;Han, Ruijun;Cero, Cheryl;Razzoli, Maria;Piaggi, Paolo;Laskowski, Lauren J;Pavlicev, Mihaela;Muglia, Louis;Mahata, Sushil K;O'Grady, Scott;McCorvy, John D;Baier, Leslie J;Sham, Yuk Y;Bartolomucci, Alessandro;
Journal Cell reports
Year 2019
DOI
S2211-1247(19)31017-4
URL
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