Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallography

Abstract

Neurokinin 1 receptor (NK1R) has key regulating functions in the central and peripheral nervous systems, and NK1R antagonists such as aprepitant have been approved for treating chemotherapy-induced nausea and vomiting. However, the lack of data on NK1R structure and biochemistry has limited further drug development targeting this receptor. Here, we combine NMR spectroscopy and X-ray crystallography to provide dynamic and static characterisation of the binding mode of aprepitant in complexes with human NK1R variants. 19F-NMR showed a slow off-rate in the binding site, where aprepitant occupies multiple substates that exchange with frequencies in the millisecond range. The environment of the bound ligand is affected by the amino acid in position 2.50, which plays a key role in ligand binding and receptor signaling in class A GPCRs. Crystal structures now reveal how receptor signaling relates to the conformation of the conserved NP7.50xxY motif in transmembrane helix VII.

Evaluation of Receptor Affinity, Analgesic Activity and Cytotoxicity of a Hybrid Peptide, AWL3020

“…Whether this is the case for AWL3020 cannot be stated as certain without further studies. A probable answer to this problem might come from molecular modelling using recently published structures of the receptor (Yin et al 2018;Schöppe et al 2019;Chen et al 2019b). We did not attempt such modelling, as the structures were unavailable at the time our study was being performed.…”

Lung innervation in the eye of a cytokine storm: neuroimmune interactions and COVID-19

“…CGRP antagonism could limit bronchoconstriction and vasodilation and limit the inflammatory response 62 , and the recent development and commercialization of anti-CGRP and anti-CGRP receptor monoclonal antibodies for the treatment of migraine might enable fast repurposing for ARDS. Similarly, neurokinin A receptor antagonists, which antagonize the binding of both neurokinin A and the closely related substance P, have been developed for clinical use against nausea and vomiting following surgery and chemotherapy 101 , 102 , and could be repurposed to counteract lung inflammation and bronchoconstriction in people with COVID-19. Nausea and vomiting, which are controlled by the area postrema, NTS and dorsal motor nucleus of the vagus, have also been reported in patients with COVID-19 and could potentially be treated with neurokinin A receptor antagonists.…”

Structure of the agonist 12–HHT in its BLT2 receptor-bound state

“…In addition to X-ray diffraction and cryo-electronic microscopy (cryo-EM) [7][8][9][10] , NMR spectroscopy can bring important information regarding conformational and energy landscapes [11][12][13][14][15][16] or, as shown here, on the structure of natural GPCR ligands in their receptor bound-states. This technique can indeed provide a detailed description of the ligand in its bound-state, at physiological temperature and with a native protein [17][18][19][20][21][22][23][24][25] . Especially with very flexible ligands, like those described in this study, NMR data can constitute the basic input to subsequent X-rayor cryo-EM-based molecular modeling of ligand/GPCR complexes.…”