9MNI

CGRP Receptor in complex with dC2_050

Summary for 9MNI

• Entry DOI: 10.2210/pdb9mni/pdb
• EMDB information: 48424
• Descriptor: Receptor activity-modifying protein 1, Calcitonin gene-related peptide type 1 receptor, De novo designed minibinder - dC2_050 (3 entities in total)
• Functional Keywords: gpcr, de novo protein design, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 81234.08

Authors

Cao, J.,Cary, B.P.,Belousoff, M.J.,Wootten, D.L. (deposition date: 2024-12-21, release date: 2025-10-22)

Primary citation

Muratspahic, E.,Feldman, D.,Kim, D.E.,Qu, X.,Bratovianu, A.M.,Rivera-Sanchez, P.,Dimitri, F.,Cao, J.,Cary, B.P.,Belousoff, M.J.,Keov, P.,Chen, Q.,Ren, Y.,Fine, J.,Sappington, I.,Schlichthaerle, T.,Zhang, J.Z.,Pillai, A.,Mihaljevic, L.,Bauer, M.,Torres, S.V.,Motmaen, A.,Lee, G.R.,Tran, L.,Wang, X.,Goreshnik, I.,Vafeados, D.K.,Svendsen, J.E.,Hosseinzadeh, P.,Lindegaard, N.,Brandt, M.,Waltenspuhl, Y.,Deibler, K.,Oostdyk, L.,Cao, W.,Anantharaman, L.,Stewart, L.,Halloran, L.,Spangler, J.B.,Sexton, P.M.,Roth, B.L.,Krumm, B.E.,Wootten, D.,Tate, C.G.,Norn, C.,Baker, D.
De novo design of miniprotein agonists and antagonists targeting G protein-coupled receptors.
Biorxiv, 2025

PubMed Abstract: G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery and development, yet the design of protein agonists and antagonists has been challenging as GPCRs are integral membrane proteins and conformationally dynamic. Here we describe computational design methods and a high throughput "receptor diversion" microscopy-based screen for generating GPCR binding miniproteins with high affinity, potency and selectivity, and the use of these methods to generate MRGPRX1 agonists and CXCR4, GLP1R, GIPR, GCGR and CGRPR antagonists. Cryo-electron microscopy data reveals atomic-level agreement between designed and experimentally determined structures for CGRPR-bound antagonists and MRGPRX1-bound agonists, confirming precise conformational control of receptor function. Our design and screening approach opens new frontiers in GPCR drug discovery and development.

PubMed: 40501737
DOI: 10.1101/2025.03.23.644666

Experimental method

ELECTRON MICROSCOPY (4.06 Å)