9HYT

Crystal structure of the GFRaL receptor in complex with an inhibitory cyclic peptide

Summary for 9HYT

• Entry DOI: 10.2210/pdb9hyt/pdb
• Descriptor: GDNF family receptor alpha-like, Inhibitory cyclic peptide, SULFATE ION, ... (6 entities in total)
• Functional Keywords: gfral, gfralpha-like, gdf15, ret, inhibitor, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 89871.85

Authors

Sandmark, J.,Ek, M. (deposition date: 2025-01-10, release date: 2025-10-22, Last modification date: 2025-11-05)

Primary citation

Noisier, A.F.M.,Sandmark, J.,Edfeldt, F.,Backmark, A.,Broddefalk, J.,Wandzik, J.,Jurva, U.,Ek, M.,Johansson, C.A.,Barlind, L.,Gunnarsson, J.,Bigalke, J.M.,Xue, Y.,Frolov, A.I.,Kankkonen, C.,Roth, R.G.,Fritsch, M.,Watcham, S.,van Rietschoten, K.,Mudd, G.E.,Harrison, H.,Chen, L.,Skynner, M.J.,Craik, D.J.,Chankeshwara, S.V.,Lemurell, M.
Design of Bicyclic Peptide Tandems Mimicking the Homodimeric GDF15 Protein to Inhibit GDF15-GFRaL-RET Complex Cell Signaling.
J.Med.Chem., 68:21441-21457, 2025

PubMed Abstract: The GDF15-GFRaL-RET signaling complex is involved in a broad range of disease states, with agonistic action of GDF15 affecting metabolism and body weight control, while inhibition is indicated in cancer and wasting disorders like cachexia. Here, we describe the discovery of the peptide inhibitors of the GDF15-GFRaL protein-protein interaction to prevent RET-induced signaling using both a structure-guided design and a phage display approach. Phage display provided bicyclic peptide hits with high affinity for GFRaL, and these were dimerized to mimic the bidentate interaction of homodimeric GDF15. Guided by structural data, the monomeric peptides were converted into tandem Bicycle molecules with picomolar affinities, similar to that of the endogenous GDF15 ligand. These dimerized protein mimetics inhibited cell signaling in a functional assay and showed improved pharmacokinetic properties compared with their monomeric counterparts. This is the first example of a homodimeric Bicycle molecule inhibiting receptor complex formation, thereby antagonizing the intracellular signaling response.

PubMed: 41066664
DOI: 10.1021/acs.jmedchem.5c01378

Experimental method

X-RAY DIFFRACTION (1.9 Å)