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National Institute of General Medical Sciences (NIGMS) and National Cancer Institute (NCI) of the National Institutes of Health (NIH)
 

A human tachykinin receptor

Figure: The tachykinin receptor ribbon structure is shown in green; the inhibitor, L760735, is shown as colored atoms

Dan Rosenbaum group (UT Southwestern Medical Center)

 

The group of Daniel Rosenbaum at UT Southwestern Medical Center determined the first crystal structure of a tachykinin G protein-coupled receptor (GPCR), the human NK1 receptor. The endogenous ligand for this receptor, Substance P, was the first neuropeptide discovered in mammals. Substance P and other tachykinin peptides communicate between the periphery and CNS, and are important mediators of pain, inflammation, and the response to noxious compounds. The Rosenbaum group crystallized the NK1 receptor with the inhibitor compound L760735, which is a close analog of the clinically used drug, aprepitant, which is used to help prevent nausea and vomiting caused by chemotherapy and surgery. The team collected data at beamline 23ID-D on lipidic cubic phase microcrystals and solved the NK1 structure at a resolution of 3.4 . The structure revealed a deep and narrow pocket occupied by the antagonist, anchored by electrostatic interactions with extracellular surface epitopes. The structure was further used as a template for computational docking and molecular dynamics simulations to predict ligand binding modes and dynamics for the drug, aprepitant. The study provides important information that may aid in the design of new treatments for cancer, pain, inflammation, and depression.

 

Citation: Yin, J, Chapman, K, Clark, LD, Shao, Z, Borek, D, Xu, Q, Wang, J,Rosenbaum, DM, Crystal structure of the human NK1 tachykinin receptor, Proc. Natl. Acad. Sci. USA 115, 13264-13269 (2018). DOI: 10.1073/pnas.1812717115


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