Article Figures & Data
Figures
- Fig. 1.
Receptor-peptide terminal group interactions in the X-ray peptide-GPCR complexes. The overview of the peptide binding is on the left side and the zoom view of the peptide terminal group interactions is on the right side. (A) Endothelin with the free C-terminal carboxylic group and ETB; (B) neurotensin with the free C-terminal carboxylic group and NTS1; (C) apelin with the free C-terminal carboxylic group and APLNR; (D) [Sar1, Ile8] angiotensin II with the free C-terminal carboxylic group and AT2; (E) DAMGO peptide with the N-terminal ammonium and MOR; (F) CVX15 with the N-terminal ammonium and CXCR4. Peptide and receptor ribbons are in red and gray, respectively. Peptide carbon atoms are in green; only receptor residues forming interactions are shown. Salt bridges and hydrogen bonds are shown in pink and black dashed lines.
- Fig. 2.
Alignment of binding site residues for human class A peptide GPCRs. (A) GPCRs binding peptides with the C-terminal free carboxyl group pointing to the helical cavity. (B) GPCRs binding peptides with the C-terminal amidated group pointing to the helical cavity. (C) GPCRs binding peptides with the N-terminus pointing to the helical cavity. (D) GPCRs binding the cyclic peptides. (E) PAR receptors. Positively charged, negatively charged, and amide-containing residues are in cyan, purple, and yellow, respectively. Receptors co-crystalized with a peptide and synthetic ligands are in gray. Residues forming direct interactions with peptides are in bold. APLNR, apelin receptor; AT1, AT2, angiotensin receptors; B1, B2, bradykinin receptors; BB1, BB2, BB3, bombesin receptors; C3a, C5a1, C5a2, complement peptide receptors; CCK1, CCK2, cholecystokinin receptors; DOR, KOR, MOR, NOP, opioid receptors; ETA, ETB, endothelin receptors; FPR1, FPR2, FPR3, N-formyl peptide receptors; GAL1, GAL2, GAL3, galanin receptors; GHSR, ghrelin receptor; GNRHR, gonadotropin-releasing hormone receptor; KISS1R, kisspeptin receptor; MC1, MC2, MC3, MC4, MC5, melanocyte-stimulating hormone receptors; MCH1, MCH2, melanin-concentrating hormone; MLNR, motilin receptor; NK1, NK2, NK3, neurokinin/tachykinin receptors; NMU1, NMU2, neuromedin-U receptors; NPBW1, NPBW2, neuropeptide B/W receptors; NPFF1, NPFF2, neuropeptide FF receptor; NPSR1, neuropeptide S receptor; NPY1, NPY2, NPY4, NPY5, neuropeptide Y receptors; NTS1, NTS2, neurotensin receptors; OX1, OX2, orexin receptors; OT, oxytocin receptor; PAR1, PAR2, PAR3, PAR4, PAR5, proteinase-activated receptors; PrRP, prolactin-releasing peptide receptor; QRFP, pyroglutamylated RFamide peptide receptor; RXFP1, RXFP2, RXFP3, RXFP4, relaxin receptors; SST1, SST2, SST3, SST4, SST5, somatostatin receptors; TRH1, thyrotropin-releasing hormone receptor; V1A, V1B, V2, vasopressin receptors; UT, urotensin receptor. Conservation score (%) for each residue position calculated from the analysis of receptor orthologs (bovine, chimpanzee, guinea pig, human, mouse, rabbit, and rat) is shown at the bottom of each binding site residue alignment. The conservation score and the corresponded bar are shown for the most conserved positively charged (cyan), negatively charged (purple) or amide-containing residues (yellow).
- Fig. 3.
Ligand binding sites of peptide GPCRs. Nonpeptide antagonist interactions with residues at positions 3.32. 4.60, and/or 6.55 in the crystal structures of NPY1, OX1, OX2, and NK1. Validated homology model of the CCK2 receptor complexed with the CCK4 peptide (Langer et al., 2005). The antagonists, the peptide CCK4, and the receptors are labeled and only the amide-containing residue is shown. Hydrogen bonding is in black-dashed lines.
Tables
- TABLE 1
Hydrogen bond (H) and salt bridge (SB) interactions between a peptide and the helical cavity from the available crystal structures of class A GPCRs bound to a peptide
Peptide Receptor Overall Number of Contacts Number of Contacts with Peptide Side Chains Number of Contacts with Peptide Backbone Number of Contacts with Peptide Terminal Group Number of Peptide Residues within the Cavity PDB Code Apelin APLNR 8 2H+1SBa 2H 2H+1SB 6 5VBL Neurotensin NTS1 6 1H 1H 3H+1SB 4 4GRV Endothelin ETB 16 4H+1SB 6H 3H+2SB 16 5GLH [Sar1, Ile8]AngII AT2 12 3H+1SB 6H 1H+1SB 6 5XJM DIPP-NH2 DOR 4 1H 2H+1SB 3 4RWD DAMGO MOR 4 1H 2H+1SB 5 6DDF CX3CL1 US28 5 1H 3H 1H 7 4XT3 CX3CL1/Nb7 US28 7 2H 4H 1H 11 4XT1 vMIP-II CXCR4 13 6H+2SB 2H 2H+1SB 9 4RWS CVX15 CXCR4 10 6H+3SB 1H 6 3OE0 cyclicPMX53 C5a1 12 6H+1SB 5H 3 6C1R ↵a Hydrogen bond criteria: 3 Å for the maximum distance between donor and acceptor atoms, 90° and 60° for donor and acceptor minimum angles, respectively. Salt bridge criteria: the maximum distance between atoms is 5 Å.
Peptide Receptor Sequence of a Peptide or Short Active Peptide Fragment (Peptide Region Important for Activity is Highlighted in Grey, Cysteine Involved in the Disulfide Bridges Are in Bold.) End Group Important for Activity Peptide Terminal End Inside the Helical Bundle Reference Angiotensin AT1, AT2 
-COOH C-end Rioux et al., 1975; Karnik 2000; Asada et al., 2018 Apelin APLNR -COOH C-end Murza et al., 2012; Ma et al., 2017 Bradykinin B1, B2 -COOH C-end Rhaleb et al., 1990; Jarnagin et al., 1996; Ha et al., 2006 Complement Peptides -COOH C-end Mollison et al., 1989; Higginbottom et al., 2005; Klos et al., 2013; Liu et al., 2018 C3a C3a C5a C5a1, C5a2 Endothelin ETA ETB -COOH C-end Rovero et al., 1990; Shihoya et al., 2016 Neurotensin NTS1, NTS2 -COOH C-end Labbe-Jullie et al., 1998; White et al., 2012; Kleczkowska and Lipkowski, 2013) C-end of Chain B Bathgate et al., 2013; Hu et al., 2017; Patil et al., 2017; Wong et al., 2018 H2 relaxin RXFP1 Insulin-like peptide 3 (INSL3) RXFP2 H3 relaxin RXFP3 C-end of Chain B INSL5 RXFP4 C-end of chain B Cholecystokinin gastrin CCK1
CCK2-CONH2 C-end Morley et al., 1965; Jensen et al., 1982; Black and Kalindjian, 2002; Archer-Lahlou et al., 2005; Dufresne et al., 2006 Orexin OX1, OX2 -CONH2 C-end Darker et al., 2001; Ammoun et al., 2003; Lang et al., 2004; Heifetz et al., 2013 Neuropeptide Y NPY1, 2, 4, and 5 -CONH2 C-end Boublik et al., 1989; Xu et al., 2013, 2018; Yang et al., 2018 Prolactin-releasing peptide PrRP -CONH2 C-end Boyle et al., 2005; Findeisen et al., 2011; Rathmann et al., 2012 Pyroglutamylated RFamide peptide QRFP -CONH2 C-end Findeisen et al., 2011 Neuropeptide FF NPFF1-2 -CONH2 C-end Findeisen et al., 2011 Metastin/kisspeptin KISS1R -CONH2 C-end Kotani et al., 2001; Findeisen et al., 2011 Vasopressin V1A, V1B, V2 -CONH2 Cyclic end Jard and Bockaert, 1975; Mouillac et al., 1995; Chini and Fanelli, 2000 Oxytocin OT -CONH2 Cyclic end Jard and Bockaert, 1975; Chini and Fanelli, 2000; Gimpl and Fahrenholz, 2001 Neuromedin B BB1 -CONH2 C-end Mervic et al., 1991; Lin et al., 1995; Jensen et al., 2008 Gastrin-relesing peptide BB2 Bombesin BB3 Neuromedin-U NMU1-2 -CONH2 C-end Brighton et al., 2004; Kawai et al., 2014 Substance-P/K, neurokinin, tachykinin NK1, NK2, NK3 -CONH2 C-end Couture et al., 1979; Ganjiwale et al., 2011 Neurokinin A Neurokinin B Thyrotropin-releasing hormone TRH1 -CONH2 All Chang et al., 1971; Engel and Gershengorn, 2007 Opioid peptides endorphins DOR, KOR, MOR, NOP H2N- N-end Morley 1983; Koehl et al., 2018 Neuropeptides B/W NPBW1-2 N-end Kanesaka et al., 2007 Neuropeptide S NPSR1 N-end Roth et al., 2006 N-formyl peptide FPR1-3 O=HC-NH- N-end Prossnitz and Ye, 1997 Adrenocorticotropic hormone MC1–5 O=HC-NH- FRW Schwyzer, 1977; Matsunaga et al., 1989; Schioth et al., 1997; Audinot et al., 2001; Haskell-Luevano et al., 2001 Melanocortins (α, β, and γ) Motilin MLNR N-end Poitras et al., 1992; Xu et al., 2005 Ghrelin GHSR N-end Charron et al., 2017 Gonadotropin-releasing hormone GNRHR CONHCHO- N-end Hoffmann et al., 2000; Padula, 2005; Barran et al., 2005 Galanin GAL1-3 H2N- N-end Church et al., 2002; Lang et al., 2015 Urotensin UT Cyclic portion Labarrere et al., 2003; Merlino et al., 2013 Melanin-concentrating hormone MCH1-2 Cyclic portion Matsunaga et al., 1989; Schioth et al., 1997; Audinot et al., 2001 Somatostatin SST1-5 Cyclic portion Vale et al., 1978; Martin-Gago et al., 2013 Fragments of a tethered ligand PAR1-4 Gerszten et al., 1994 BB1, BB2, BB3, bombesin receptors; C3a, C5a1, C5a2, complement peptide receptors; CCK1, CCK2, cholecystokinin receptors; ETA, ETB, endothelin receptors; FPR1, FPR2, FPR3, N-formyl peptide receptors; GAL1, GAL2, GAL3, galanin receptors; GHSR, ghrelin receptor; GNRHR, gonadotropin-releasing hormone receptor; MC5, melanocyte-stimulating hormone receptor; MCH1, MCH2, melanin-concentrating hormone receptors; MLNR, motilin receptor; NPBW1, NPBW2, neuropeptide B/W receptors; NPFF1, NPFF2, neuropeptide FF receptor; NPSR1, neuropeptide S receptor; PrRP, prolactin-releasing peptide receptor; QRFP, pyroglutamylated RFamide peptide receptor; SST1, SST2, SST3, SST4, SST5, somatostatin receptors; TRH1, thyrotropin-releasing hormone receptor; UT, urotensin receptor; V1A, V1B, V2, vasopressin receptors.
In this issue
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- Article
- Abstract
- Introduction
- X-Ray Structures of GPCRs Bound to Peptides
- Class A Receptor Grouping with Peptide SAR and Hydrophilic Binding Site Residues as a Basis
- GPCRs Binding Peptides with the C-Terminal Free Carboxyl Group Interacting with the Helical Cavity
- GPCRs Binding Peptides with the C-Terminal Amidated Carboxyl Group Interacting with the Helical Cavity
- GPCRs Binding Peptides with the N-Terminal End Pointing to the Helical Bundle
- GPCRs Binding Cyclic Peptides with a Cyclic Part Important for Activity and the PAR Receptors
- Concluding Remarks
- Acknowledgments
- Authorship Contributions
- Footnotes
- Abbreviations
- References
- Figures & Data
- Info & Metrics
- eLetters