Abstract:The neuropeptide Substance P (SP) is important in pain and inflammation. SP activates the neurokinin-1 receptor (NK1R) to signal via G
q
and G
s
proteins. Neurokinin A also activates NK1R, but leads to selective G
q
signaling. How two stimuli yield distinct G protein signaling at the same G protein-coupled receptor remains unclear. We determined cryo-EM structures of active NK1R bound to SP or the G
q
-biased peptide SP… Show more
“…Most recently, solved structures of receptors bound to nucleotide-free G proteins have been used to predict residues in the receptor-G protein interface that contribute to selectivity. These studies have provided valuable insights into how individual receptors discriminate G protein subtypes, and collectively suggest that the conformation of the receptor-G protein complexes that are critical for selective coupling share many features with these empty-state complexes [5][6][7][8] . Nevertheless, it is recognized that structural studies are generally limited to stable complexes that exist only after GDP release, and that such complexes may not reflect the key intermediates that immediately precede nucleotide release.…”
Section: Discussionmentioning
confidence: 99%
“…The mechanistic basis of coupling selectivity has been studied extensively using receptor and G protein chimeras and site-directed mutagenesis 3,4 . More recently, structural characterization of GPCR-G protein complexes has identified elements that are important for activation of specific G proteins [5][6][7][8] . However, structural studies require stable agonist-receptor-G protein ternary complexes, and this almost always requires a nucleotide-free G protein.…”
G protein-coupled receptors (GPCRs) selectively activate at least one of the four families of heterotrimeric G proteins to transduce environmental cues, but the mechanistic basis of coupling selectivity remains unclear. Structural studies have emphasized structural complementarity of GPCR complexes with nucleotide-free G proteins, but it has also been suggested that selectivity may be determined by intermediate activation processes that occur prior to nucleotide release. To test these ideas we have studied coupling to nucleotide-decoupled G protein variants, which can adopt conformations similar to receptor-bound G proteins without the need for nucleotide release. We find that selectivity is significantly degraded when nucleotide release is not required for GPCR-G protein complex formation, to the extent that most GPCRs interact with most nucleotide-decoupled G proteins. These findings demonstrate the absence of absolute structural incompatibility between most GPCRs and G proteins, and are consistent with the hypothesis that high-energy intermediate state complexes are involved in coupling selectivity.
“…Most recently, solved structures of receptors bound to nucleotide-free G proteins have been used to predict residues in the receptor-G protein interface that contribute to selectivity. These studies have provided valuable insights into how individual receptors discriminate G protein subtypes, and collectively suggest that the conformation of the receptor-G protein complexes that are critical for selective coupling share many features with these empty-state complexes [5][6][7][8] . Nevertheless, it is recognized that structural studies are generally limited to stable complexes that exist only after GDP release, and that such complexes may not reflect the key intermediates that immediately precede nucleotide release.…”
Section: Discussionmentioning
confidence: 99%
“…The mechanistic basis of coupling selectivity has been studied extensively using receptor and G protein chimeras and site-directed mutagenesis 3,4 . More recently, structural characterization of GPCR-G protein complexes has identified elements that are important for activation of specific G proteins [5][6][7][8] . However, structural studies require stable agonist-receptor-G protein ternary complexes, and this almost always requires a nucleotide-free G protein.…”
G protein-coupled receptors (GPCRs) selectively activate at least one of the four families of heterotrimeric G proteins to transduce environmental cues, but the mechanistic basis of coupling selectivity remains unclear. Structural studies have emphasized structural complementarity of GPCR complexes with nucleotide-free G proteins, but it has also been suggested that selectivity may be determined by intermediate activation processes that occur prior to nucleotide release. To test these ideas we have studied coupling to nucleotide-decoupled G protein variants, which can adopt conformations similar to receptor-bound G proteins without the need for nucleotide release. We find that selectivity is significantly degraded when nucleotide release is not required for GPCR-G protein complex formation, to the extent that most GPCRs interact with most nucleotide-decoupled G proteins. These findings demonstrate the absence of absolute structural incompatibility between most GPCRs and G proteins, and are consistent with the hypothesis that high-energy intermediate state complexes are involved in coupling selectivity.
“…S3 ). In the structure of the NKA-bound NK2R–G q complex, ECL2 mainly interacts with the first two N-terminal residues His1 and Lys2 of NKA, while in the recently reported SP-bound NK1R–G q structure, R177 of ECL2 forms an extended hydrogen-bond interaction with the side chain of N96 2.68 and the main-chain carbonyl oxygen of Gln6 of SP 8 , 9 (Fig. 1l ).…”
mentioning
confidence: 87%
“…The N-termini of tachykinins are critical regions associated with their subtype selectivity 8 . The structure shows that the N-terminus of NKA is mainly stabilized by ECL2 of the receptor (Fig.…”
One of the strategies in the search for safe and effective analgesic drugs is the design of multitarget analgesics. Such compounds are intended to have high affinity and activity at more than one molecular target involved in pain modulation. In the present contribution we summarize the attempts in which fentanyl or its substructures were used as a μ-opioid receptor pharmacophoric fragment and a scaffold to which fragments related to non-opioid receptors were attached. The non-opioid ‘second’ targets included proteins as diverse as imidazoline I2 binding sites, CB1 cannabinoid receptor, NK1 tachykinin receptor, D2 dopamine receptor, cyclooxygenases, fatty acid amide hydrolase and monoacylglycerol lipase and σ1 receptor. Reviewing the individual attempts, we outline the chemistry, the obtained pharmacological properties and structure-activity relationships. Finally, we discuss the possible directions for future work.
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