Molecular and functional analysis of human ?-defensin 3 action at melanocortin receptors.

ABSTRACT: The ?-defensins are a class of small, cationic proteins first recognized as antimicrobial components of the innate and adaptive immune system. More recently, one of the major ?-defensins produced in skin, ?-defensin 3, has been discovered to function as a melanocortin receptor ligand in vivo and in vitro, but its biophysical and pharmacological basis of action has been enigmatic. Here, we report functional and biochemical studies focused on human ?-defensin 3 (HBD3) and melanocortin receptors 1 and 4. Genetic and pharmacologic studies indicate that HBD3 acts as a neutral melanocortin receptor antagonist capable of blocking the action of either stimulatory agonists such as ?-melanocyte stimulating hormone or inhibitory inverse agonists such as Agouti signaling protein (ASIP) and Agouti-related protein (AGRP). A comprehensive structure-function analysis demonstrates that two patches of positively charged residues, located on opposite poles of HBD3 and spatially organized by the compact ?-defensin fold, are primarily responsible for high-affinity binding to melanocortin receptors. These findings identify a distinct mode of melanocortin receptor-ligand interactions based primarily on electrostatic complementarity, with implications for designing ligands that target melanocortin and potentially other seven transmembrane receptors.

SUBMITTER: Nix MA 

PROVIDER: S-EPMC3714013 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature