The neurotensin receptor 1 (NTSR1) is a G-protein-coupled receptor (GPCR) that engages multiple G-protein subtypes and is involved in regulation of blood pressure, body temperature, weight, and response to pain. Here we present 3-Å structures of the human NTSR1 in complex with the agonist JMV449 and the heterotrimeric G i1 protein in two conformations (C state and NC Reprints and permissions information is available at www.nature.com/reprints.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Biased agonists of G protein–coupled receptors (GPCRs) preferentially activate a subset of downstream signaling pathways. In this work, we present crystal structures of angiotensin II type 1 receptor (AT1R) (2.7 to 2.9 angstroms) bound to three ligands with divergent bias profiles: the balanced endogenous agonist angiotensin II (AngII) and two strongly β-arrestin–biased analogs. Compared with other ligands, AngII promotes more-substantial rearrangements not only at the bottom of the ligand-binding pocket but also in a key polar network in the receptor core, which forms a sodium-binding site in most GPCRs. Divergences from the family consensus in this region, which appears to act as a biased signaling switch, may predispose the AT1R and certain other GPCRs (such as chemokine receptors) to adopt conformations that are capable of activating β-arrestin but not heterotrimeric Gq protein signaling.
Biased signaling, in which different ligands that bind to the same G protein–coupled receptor preferentially trigger distinct signaling pathways, holds great promise for the design of safer and more effective drugs. Its structural mechanism remains unclear, however, hampering efforts to design drugs with desired signaling profiles. Here, we use extensive atomic-level molecular dynamics simulations to determine how arrestin bias and G protein bias arise at the angiotensin II type 1 receptor. The receptor adopts two major signaling conformations, one of which couples almost exclusively to arrestin, whereas the other also couples effectively to a G protein. A long-range allosteric network allows ligands in the extracellular binding pocket to favor either of the two intracellular conformations. Guided by this computationally determined mechanism, we designed ligands with desired signaling profiles.
The conversion of light energy into ion gradients across biological membranes is one of the most fundamental reactions in primary biological energy transduction. Recently, the structure of the first light-activated Na + pump, Krokinobacter eikastus rhodopsin 2 (KR2), was resolved at atomic resolution [Kato HE, et al. (2015) Nature 521: [48][49][50][51][52][53]. To elucidate its molecular mechanism for Na + pumping, we perform here extensive classical and quantum molecular dynamics (MD) simulations of transient photocycle states. Our simulations show how the dynamics of key residues regulate water and ion access between the bulk and the buried light-triggered retinal site. We identify putative Na + binding sites and show how protonation and conformational changes gate the ion through these sites toward the extracellular side. We further show by correlated ab initio quantum chemical calculations that the obtained putative photocycle intermediates are in close agreement with experimental transient optical spectroscopic data. The combined results of the ion translocation and gating mechanisms in KR2 may provide a basis for the rational design of novel light-driven ion pumps with optogenetic applications.bacterial ion pumps | bioenergetics | QM/MM | optogenetics | retinal P rimary biological energy conversion is based on the efficient capture and conversion of light and chemical energy into ion gradients across biological membranes (1, 2). The established gradients are used to thermodynamically drive energy-requiring processes, such as active transport and synthesis of adenosine triphosphate (ATP) (3, 4). The rhodopsin family of proteins catalyzes such reactions by harnessing the energy from retinal photoisomerization and deprotonation reactions, followed by conformational changes that further trigger the pumping of ions across the membrane (5). All previously known ion-pumping rhodopsins function either as inward chloride or outward proton pumps, but the structure of the first Na + pumping rhodopsin, Krokinobacter eikastus rhodopsin 2 (KR2) (6), was recently resolved (7,8). In the absence of Na + ions, KR2 functions as an outward proton pump, similarly to bacteriorhodopsin (bR), but under physiological conditions, KR2 pumps Na + out of the cell (6, 9).KR2 shares the heptahelical transmembrane (7TM) structure common to all microbial rhodopsins (Fig. 1A) (5,7,8). In contrast to bR, however, where a highly conserved Asp-Thr-Asp (DTD) motif is used to pump protons, KR2 employs a unique NDQ motif comprising residues Asn112, Asp116, and Gln123 (6). In bR, Asp85 and Asp96 function as proton acceptors and donors for the protonated Schiff base (PSB), respectively, whereas in KR2, Asn112 and Gln123 occupy these positions, and Asp116 replaces Thr89. In analogy to bR, it has been suggested that Gln123 aids in capturing ions from the solvent and that Asn112 might be part of a Na + binding site (6,10).Similarly to other microbial rhodopsins, four photocycle intermediates have been spectroscopically identified in KR2 (Fig. 1B) (6)...
Chlorophylls are light-capturing units found in photosynthetic proteins. We study here the ground and excited state properties of monomeric, dimeric, and tetrameric models of the special chlorophyll/bacteriochlorophyll (Chl/BChl) pigment (P) centers P700 and P680/P870 of type I and type II photosystems, respectively. In the excited state calculations, we study the performance of the algebraic diagrammatic construction through second-order (ADC(2)) method in combination with the reduced virtual space (RVS) approach and the recently developed Laplace-transformed scaled-opposite-spin (LT-SOS) algorithm, which allows us, for the first time, to address multimeric effects at correlated ab initio levels using large basis sets. At the LT-SOS-RVS-ADC(2)/def2-TZVP level, we obtain vertical excitation energies (VEEs) of 2.00-2.07 and 1.52-1.62 eV for the P680/P700 and the P870 pigment models, respectively, which agree well with the experimental absorption maxima of 1.82, 1.77, and 1.43 eV for P680, P700, and P870, respectively. In the P680/P870 models, we find that the photoexcitation leads to a π → π* transition in which the exciton is delocalized between the adjacent Chl/BChl molecules of the central pair, whereas the exciton is localized to a single chlorophyll molecule in the P700 model. Consistent with experiments, the calculated excitonic splittings between the central pairs of P680, P700, and P870 models are 80, 200, and 400 cm(-1), respectively. The calculations show that the electron affinity of the radical cation of the P680 model is 0.4 V larger than for the P870 model and 0.2 V larger than for P700. The chromophore stacking interaction is found to strongly influence the electron localization properties of the light-absorbing pigments, which may help to elucidate mechanistic details of the charge separation process in type I and type II photosystems.
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 SP6–11. Peptide interactions deep within NK1R are critical for receptor activation. Conversely, interactions between SP and NK1R extracellular loops are required for potent G s signaling but not G q signaling. Molecular dynamics simulations showed that these superficial contacts restrict SP flexibility. SP6–11, which lacks these interactions, is dynamic while bound to NK1R. Structural dynamics of NK1R agonists therefore depend on interactions with the receptor extracellular loops and regulate G protein signaling selectivity. Similar interactions between other neuropeptides and their cognate receptors may tune intracellular signaling.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.