Integrative In-Silico and Evolutionary Analysis of the Human Leptin Receptor CRH2 Domain for Therapeutic Targeting

Reji Manjunathan; Nalini Devarajan; Malathi Ragunathan; Raskin Erusan Rajagopal

Abstract

Leptin mediates various cellular processes through its receptor (OB-Rb) located on the cell membrane. The leptin receptor (LR) belongs to the Class 1 cytokine receptor family, characterised by four cysteine receptor homology domains (CRH). The three-dimensional structure of the leptin receptor has enhanced understanding of its atomic interactions with leptin. Further insights into the evolutionary significance and the relationship between leptin and its receptor improve therapeutic targeting of various diseases involving the leptin-leptin receptor axis. Therefore, in the present study, we aimed to analyse the evolutionary relationship of LR and to confirm its structure and function. The presence of four cysteine residues in the extracellular domain results in high peptide sequence homology among humans, monkeys, rats, and mice. The conserved leucine helps maintain the hydrophobic character of LR, and the disulfide bonds uphold the structural integrity of LR’s binding sites. The extracellular domain of human LR comprises seven structural domains, including the conserved BOX1 and BOX II motifs. A detailed analysis of the molecular interaction between leptin and CRH2, along with the identification of key residues, aids in the selection of selective LR agonists and antagonists for therapeutic purposes.

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