22XC

Structure of CXCR4 in complex with a de-novo designed mini-protein antagonist

Summary for 22XC

• Entry DOI: 10.2210/pdb22xc/pdb
• EMDB information: 68747
• Descriptor: dCX001 binder antagonist, C-X-C chemokine receptor type 4, CHOLESTEROL, ... (4 entities in total)
• Functional Keywords: gpcr, g protein, signaling protein, signaling protein-immune system complex
• Biological source: synthetic construct; More
• Total number of polymer chains: 6
• Total formula weight: 170235.51

Authors

Banerjee, R.,Ganguly, M.,Banerjee, N.,Tiwari, D.,Muratspahic, E.,Baker, D.,Shukla, A.K. (deposition date: 2026-01-26, release date: 2026-04-22, Last modification date: 2026-06-03)

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.,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.,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, 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 (3.28 Å)