Molecular and Functional Analysis of Human β-Defensin 3 Action at Melanocortin Receptors
| Autor: | Gregory S. Barsh, Tina Ta, Christopher B. Kaelin, Glenn L. Millhauser, Allison Weis, Matthew A. Nix, Gregory J. Morton |
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| Rok vydání: | 2013 |
| Předmět: |
beta-Defensins
Molecular Sequence Data Static Electricity Clinical Biochemistry Mice Transgenic Plasma protein binding Biology Ligands Biochemistry Article Mice Melanocortin receptor Drug Discovery Inverse agonist Animals Humans Agouti-Related Protein Amino Acid Sequence Receptor Defensin Molecular Biology Pharmacology integumentary system digestive oral and skin physiology General Medicine Melanocortin 3 receptor Protein Structure Tertiary Mice Inbred C57BL Beta defensin Mutation Agouti Signaling Protein Receptor Melanocortin Type 4 Molecular Medicine Melanocortin Receptor Melanocortin Type 1 hormones hormone substitutes and hormone antagonists Protein Binding |
| Zdroj: | Chemistry & Biology. 20(6):784-795 |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/j.chembiol.2013.04.015 |
| Popis: | SummaryThe β-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 β-defensins produced in skin, β-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 β-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 α-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 β-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. |
| Databáze: | OpenAIRE |
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