6E59

Crystal structure of the human NK1 tachykinin receptor

Summary for 6E59

• Entry DOI: 10.2210/pdb6e59/pdb
• Descriptor: Substance-P receptor, GlgA glycogen synthase, Substance-P receptor chimera, 1-(4-{[(2R,3S)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)morpholin-4-yl]methyl}-1H-1,2,3-triazol-5-yl)-N,N-dimethylmethanamine (2 entities in total)
• Functional Keywords: g protein-coupled receptor fusion protein, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 62449.70

Authors

Yin, J.,Clark, L.,Chapman, K.,Shao, Z.,Borek, D.,Xu, Q.,Wang, J.,Rosenbaum, D.M. (deposition date: 2018-07-19, release date: 2018-12-12, Last modification date: 2023-10-11)

Primary citation

Yin, J.,Chapman, K.,Clark, L.D.,Shao, Z.,Borek, D.,Xu, Q.,Wang, J.,Rosenbaum, D.M.
Crystal structure of the human NK1tachykinin receptor.
Proc. Natl. Acad. Sci. U.S.A., 115:13264-13269, 2018

PubMed Abstract: The NK tachykinin G-protein-coupled receptor (GPCR) binds substance P, the first neuropeptide to be discovered in mammals. Through activation of NKR, substance P modulates a wide variety of physiological and disease processes including nociception, inflammation, and depression. Human NKR (hNKR) modulators have shown promise in clinical trials for migraine, depression, and emesis. However, the only currently approved drugs targeting hNKR are inhibitors for chemotherapy-induced nausea and vomiting (CINV). To better understand the molecular basis of ligand recognition and selectivity, we solved the crystal structure of hNKR bound to the inhibitor L760735, a close analog of the drug aprepitant. Our crystal structure reveals the basis for antagonist interaction in the deep and narrow orthosteric pocket of the receptor. We used our structure as a template for computational docking and molecular-dynamics simulations to dissect the energetic importance of binding pocket interactions and model the binding of aprepitant. The structure of hNKR is a valuable tool in the further development of tachykinin receptor modulators for multiple clinical applications.

PubMed: 30538204
DOI: 10.1073/pnas.1812717115

Experimental method

X-RAY DIFFRACTION (3.4 Å)