9CIB
CryoEM Structure of HCA2 DREADD Gi1 in complex with FCH-2296413 (Local Refinement)
Summary for 9CIB
| Entry DOI | 10.2210/pdb9cib/pdb |
| Related | 8UUJ |
| EMDB information | 45616 |
| Descriptor | Hydroxycarboxylic acid receptor 2, (3M,4aR,5aR)-3-(1H-tetrazol-5-yl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazole (2 entities in total) |
| Functional Keywords | gpcr, hca2, membrane protein, dreadd |
| Biological source | Mus musculus (house mouse) |
| Total number of polymer chains | 1 |
| Total formula weight | 34435.92 |
| Authors | Krumm, B.E.,Kang, H.J.,Diberto, J.F.,Kapolka, N.J.,Gumpper, R.H.,Olsen, R.H.J.,Huang, X.P.,Zhang, S.,Fay, J.F.,Roth, B.L. (deposition date: 2024-07-03, release date: 2025-05-14) |
| Primary citation | Kang, H.J.,Krumm, B.E.,Tassou, A.,Geron, M.,DiBerto, J.F.,Kapolka, N.J.,Gumpper, R.H.,Sakamoto, K.,Dewran Kocak, D.,Olsen, R.H.J.,Huang, X.P.,Zhang, S.,Huang, K.L.,Zaidi, S.A.,Nguyen, M.T.,Jo, M.J.,Katritch, V.,Fay, J.F.,Scherrer, G.,Roth, B.L. Structure-guided design of a peripherally restricted chemogenetic system. Cell, 187:7433-7449.e20, 2024 Cited by PubMed Abstract: Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remotely controlling cellular signaling, neural activity, behavior, and physiology. Using a structure-guided approach, we provide a peripherally restricted Gi-DREADD, hydroxycarboxylic acid receptor DREADD (HCAD), whose native receptor is minimally expressed in the brain, and a chemical actuator that does not cross the blood-brain barrier (BBB). This was accomplished by combined mutagenesis, analoging via an ultra-large make-on-demand library, structural determination of the designed DREADD receptor via cryoelectron microscopy (cryo-EM), and validation of HCAD function. Expression and activation of HCAD in dorsal root ganglion (DRG) neurons inhibit action potential (AP) firing and reduce both acute and tissue-injury-induced inflammatory pain. The HCAD chemogenetic system expands the possibilities for studying numerous peripheral systems with little adverse effects on the central nervous system (CNS). The structure-guided approach used to generate HCAD also has the potential to accelerate the development of emerging chemogenetic tools for basic and translational sciences. PubMed: 39631393DOI: 10.1016/j.cell.2024.11.001 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.62 Å) |
Structure validation
Download full validation report
