Satiety in the gut is regulated by thenervous system. The melanocortin-4 receptor (MC4R) in the hypothalamus is knownas the brain’s “switchboard” to control appetite and metabolism. It is apopular target for the treatment of such metabolic diseases as obesity byregulating the body’s energy metabolism and eating behavior in response to thesimulation of proopiomelanocortin (POMC) and agouti-related peptide (AgRP) byvarious metabolic signals such as leptin and neuropeptide Y. MC4R belongs tothe melanocortin receptor family, a group of five (MC1R−MC5R) class A Gprotein-coupled receptors (GPCRs) and is primarily coupled to the stimulatory Gprotein (Gs) and increases intracellular cyclic adenosine monophosphate (cAMP) accumulation.However, the five members of this family are highly conserved in amino acidsequence and they recognize identical or very similar peptide ligands. Owing tothe exceptional sequence homology among MCRs, most peptidic agonists initiallydeveloped for MC4R lack the capability of avoiding cross-reactivity with otherMCR subtypes, such as MC1R, leading to adverse effects, e.g., skin pigmentationand nausea. Thus, it is of immense necessity to address the heterogeneity ofthe receptor in developing drugs targeting MC4R.
The research team led by Prof. ZHANG Yanfrom the Zhejiang University School of Medicine and the research team led byWANG Mingwei from the Fudan University Department of Pharmacology conductedcollaborative research in this field. Their research findings were published inan article titled “Structural insights into ligand recognition and activationof the melanocortin-4 receptor” in the journal Cell Research on August 25.
Cryo-EMstructures of the MC4R–Gs complexes
Researchers employed single-particlecryo-electron microscopy (cryo-EM) to determine four structures of the humanMC4R−Gs complexes: three bound to α-MSH, afamelanotide or bremelanotide at theresolutions of 3.0 Å, 3.0 Å and 3.1 Å, respectively; and one bound to THIQ atthe resolution of 3.1 Å. These structures reveal the molecular basis of ligandrecognition and receptor activation for MC4R, shed light on the subtype selectivityof MCRs, and provide templates for the rational design of novel therapeuticstargeting MC4R to treat obesity.
Selectiveactivation of MC4R by THIQ
The amino acid sequence of MCRs is highlyconserved. Except MC2R, the other four MCRs, which are endogenously activatedby melanocyte-stimulating hormones (MSH), are virtually non-selective.Researchers made a detailed analysis of the structural basis of the selectivityof THIQ, a small-molecule agonist initially developed by Merck in 2005. Bycomparing the structure of MC4R and homology-modeled MC1R, they discovered thatthree amino acids interact differently with THIQ in the two receptors.Subsequent experiments revealed that the combination of these 3 amino acidsplayed a vital role in THIQ selectivity. In addition, researchers alsoidentified more concentrated regions of non-conserved amino acid aggregationthat could be instrumental for the development of selective ligands.
“These results offer unprecedented structural insightsinto the pharmacological and signaling features of MC4R and deepen theunderstanding of how naturally occurring mutants of MC4R modify the receptoractivity,” said Prof. Zhang. “Our research will serve as a structural templatefor rational drug design targeting the leptin-melanocortin pathway andfacilitate the discovery of novel therapeutics against obesity.”
