期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 293, 期 41, 页码 15777-15789出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.002645
关键词
relaxin; G protein-coupled receptor (GPCR); site-directed mutagenesis; molecular modeling; molecular docking; relaxin-3; RXFP3
资金
- National Health and Medical Research Council (NHMRC) of Australia [1066369, 1065481]
- Victorian Government Operational Infrastructure Support Program
- Melbourne Research Scholarship (MRS)
- Melbourne International Fee Remission Scholarship (MIFRS)
- NHMRC Dementia Fellowship
- Australian Research Council Future Fellowship
- NHMRC Research Fellowship
- National Health and Medical Research Council of Australia [1066369, 1065481] Funding Source: NHMRC
The relaxin-3 neuropeptide activates the relaxin family peptide 3 (RXFP3) receptor to modulate stress, appetite, and cognition. RXFP3 shows promise as a target for treating neurological disorders, but realization of its clinical potential requires development of smaller RXFP3-specific drugs that can penetrate the blood-brain barrier. Designing such drugs is challenging and requires structural knowledge of agonist- and antagonist-binding modes. Here, we used structure-activity data for relaxin-3 and a peptide RXFP3 antagonist termed R3 B1-22R to guide receptor mutagenesis and develop models of their binding modes. RXFP3 residues were alanine-substituted individually and in combination and tested in cell-based binding and functional assays to refine models of agonist and antagonist binding to active- and inactive-state homology models of RXFP3, respectively. These models suggested that both agonists and antagonists interact with RXFP3 via similar residues in their B-chain central helix. The models further suggested that the B-chain Trp(27) inserts into the binding pocket of RXFP3 and interacts with Trp(138) and Lys(271), the latter through a salt bridge with the C-terminal carboxyl group of Trp(27) in relaxin-3. R3 B1-22R, which does not contain Trp(27), used a non-native Arg(23) residue to form cation-pi and salt-bridge interactions with Trp(138) and Glu(141) in RXFP3, explaining a key contribution of Arg(23) to affinity. Overall, relaxin-3 and R3 B1-22R appear to share similar binding residues but may differ in binding modes, leading to active and inactive RXFP3 conformational states, respectively. These mechanistic insights may assist structure-based drug design of smaller relaxin-3 mimetics to manage neurological disorders.
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