9MM5

CGRP Receptor in complex with dC2_049

Summary for 9MM5

• Entry DOI: 10.2210/pdb9mm5/pdb
• EMDB information: 48385
• Descriptor: De novo designed minibinder - dC2_049, Receptor activity-modifying protein 1, Calcitonin gene-related peptide type 1 receptor (3 entities in total)
• Functional Keywords: gpcr, denovo protein design, membrane protein
• Biological source: synthetic construct; More
• Total number of polymer chains: 3
• Total formula weight: 81311.30

Authors

Cao, J.,Cary, B.P.,Belousoff, M.J.,Wootten, D.L. (deposition date: 2024-12-19, release date: 2026-01-28, Last modification date: 2026-09-09)

Primary citation

Muratspahic, E.,Feldman, D.,Kim, D.E.,Qu, X.,Bratovianu, A.M.,Rivera-Sanchez, P.,Voss, J.H.,Hertz, E.P.T.,Jeppesen, M.,Dimitri, F.,Sakamoto, K.,Nallathambi, A.,Peceli, P.,Cao, J.,Cary, B.P.,Belousoff, M.J.,Keov, P.,Trinh, P.N.H.,Chen, Q.,Ren, Y.,Fine, J.,Mishra, S.,Dalal, A.,Sinha, S.,Banerjee, R.,Ganguly, M.,Karuppusamy, K.V.,Sappington, I.,Schlichthaerle, T.,Zhang, J.Z.,Pillai, A.,Coventry, B.,Mihaljevic, L.,Bauer, M.S.,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.,Deweid, L.,Bennett, A.,Schoppe, J.,Dong, T.,Yan, X.,Oostdyk, L.,Cao, W.,Anantharaman, L.,Weisser, J.J.,Bastlund, J.F.,Bundgaard, C.,Asuni, A.A.,English, J.G.,Stewart, L.J.,Halloran, L.,Spangler, J.B.,Lieber, A.,Shukla, A.K.,Sexton, P.M.,Roth, B.L.,Krumm, B.E.,Wootten, D.,Tate, C.G.,Norn, C.,Baker, D.
De novo design of miniproteins targeting GPCRs.
Nature, 656:1044-1053, 2026

PubMed Abstract: G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery and development, but the design of protein agonists and antagonists has been challenging as GPCRs are integral membrane proteins and conformationally dynamic. Here we describe computational de novo design methods and a high-throughput "receptor diversion" microscopy-based screen for generating GPCR binding miniproteins with high affinity, potency and selectivity. We design miniprotein agonists that activate receptors involved in itch and pain, as well as antagonists that inhibit receptors implicated in cancer, metabolic disorders such as diabetes and obesity, and migraine. Cryo-electron microscopy (cryo-EM) structures of five receptor-bound designs are close to the computational design models. A designed chemokine receptor antagonist mobilizes hematopoietic stem and progenitor cells in vivo at a level comparable to a clinically used drug, with fewer adverse effects.

PubMed: 42168559
DOI: 10.1038/s41586-026-10656-8

Experimental method

ELECTRON MICROSCOPY (3.26 Å)