Abstract:The NK1 tachykinin G-protein–coupled receptor (GPCR) binds substance P, the first neuropeptide to be discovered in mammals. Through activation of NK1R, substance P modulates a wide variety of physiological and disease processes including nociception, inflammation, and depression. Human NK1R (hNK1R) modulators have shown promise in clinical trials for migraine, depression, and emesis. However, the only currently approved drugs targeting hNK1R are inhibitors for chemotherapy-induced nausea and vomiting (CINV). T… Show more
“…In contrast, the interaction between D/N78 2.50 and S119 3.39 , which is thought to be important for the allosteric modulation of many class A GPCRs 17,27 , is relatively weak in the two NK1R structures (3.8 Å for the N78 2.50 and 3.3 Å for the D78 2.50 structures), suggesting that S119 3.39 may play a less critical role in NK1R activation. Compared to another recently solved NK1R structure with glutamic acid at 2.50 position 28 , the side chain of E 2.50 further extends toward the N301 7.49 and further away from S119 3.39 , in agreement with our speculation.Fig. 3Interaction modes of the residues at positions 2.50 and 7.49 and functional assays of NK1R mutants.…”
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.
“…In contrast, the interaction between D/N78 2.50 and S119 3.39 , which is thought to be important for the allosteric modulation of many class A GPCRs 17,27 , is relatively weak in the two NK1R structures (3.8 Å for the N78 2.50 and 3.3 Å for the D78 2.50 structures), suggesting that S119 3.39 may play a less critical role in NK1R activation. Compared to another recently solved NK1R structure with glutamic acid at 2.50 position 28 , the side chain of E 2.50 further extends toward the N301 7.49 and further away from S119 3.39 , in agreement with our speculation.Fig. 3Interaction modes of the residues at positions 2.50 and 7.49 and functional assays of NK1R mutants.…”
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.
“…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.…”
In the present contribution we report design, synthesis and evaluation of receptor affinity, analgesic activity and cytotoxicity of a hybrid peptide, AWL3020. The peptide includes two pharmacophores, one of δ-opioid receptor (δOR) agonists and one of neurokinin-1 receptor (NK1R) antagonists. The design was motivated by the desire to obtain a compound with strong analgesic action and potential additional antiproliferative action. The compound displays high δOR affinity (IC 50 = 29.5 nM). On the other hand, it has only poor affinity for the NK1R (IC 50 = 70.28 μM). The substance shows good analgesic action which is however weaker than that of morphine. Regarding the effect on proliferation, the compound exhibits no pro-proliferative action in the assayed range. In higher concentrations, it has also cytotoxic activity. This effect is however not selective. The strongest effect of AWL3020 was found for melanoma MeW164 cell line (EC 50 = 46.27 μM in reduction of cell numbers after a few days of incubation; EC 50 = 37.78 μM in MTT assay).
“…The crystal structures of the following class A peptide-GPCRs complexed with peptide agonists or antagonists are currently available: apelin (APLNR), angiotensin (AT 1 ), neurotensin (NTS 1 ), endothelin (ET B ), opioid (MOR and DOR), chemokine (US28 and CXCR4), and component peptide (C5a 1 ) receptors (Wu et al, 2010;White et al, 2012;Burg et al, 2015;Fenalti et al, 2015;Qin et al, 2015;Shihoya et al, 2016;Ma et al, 2017;Asada et al, 2018;Koehl et al, 2018;Liu et al, 2018). Furthermore, subtypes of the protease-activated (PAR1 and PAR2), chemokine (CXCR4, CCR2, CCR5 and CCR9), opioid (MOR, KOR, DOR, and NOP), orexin (OX 1 and OX 2 ), angiotensin (AT 1 and AT 2 ), neuropeptide (NPY1), C5a, and neurokinin (NK 1 ) receptors are crystallized in complex with nonpeptide orthosteric and/or allosteric antagonists (Wu et al, 2017;Liu et al, 2018;Robertson et al, 2018;Yang et al, 2018;Yin et al, 2018;Schoppe et al, 2019).…”
Section: X-ray Structures Of Gpcrs Bound To Peptidesmentioning
confidence: 99%
“…However, the amidecontaining residue at position 4.60, which is conserved within the subfamily, forms a hydrogen bond with the antagonists aprepitant (Fig. 2), CP-99,994, and netupitant in the NK 1 crystal structure complexes (Yin et al, 2018;Schoppe et al, 2019) and has been predicted to bind to the neurokinin C-terminus according to mutagenesis and modeling studies (Lundstrom et al, 1997).…”
Section: Gpcrs Binding Peptides With the C-terminal Amidated Carboxylmentioning
Many physiologic processes are controlled through the activation of G protein-coupled receptors (GPCRs) by regulatory peptides, making peptide GPCRs particularly useful targets for major human diseases such as diabetes and cancer. Peptide GPCRs are also being evaluated as next-generation targets for the development of novel antiparasite agents and insecticides in veterinary medicine and agriculture. Resolution of crystal structures for several peptide GPCRs has advanced our understanding of peptide-receptor interactions and fueled interest in correlating peptide heterogeneity with receptor-binding properties. In this review, the knowledge of recently crystalized peptide-GPCR complexes, previously accumulated peptide structure-activity relationship studies, receptor mutagenesis, and sequence alignment are integrated to better understand peptide binding to the transmembrane cavity of class A GPCRs. Using SAR data, we show that peptide class A GPCRs can be divided into groups with distinct hydrophilic residues. These characteristic residues help explain the preference of a receptor to bind the C-terminal free carboxyl group, the C-terminal amidated group, or the N-terminal ammonium group of peptides.
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