Table 4.
Residues involved in the interaction of ligands with potential GPCR-derived therapeutic targets of PD for which structural data information is available on PDB.
| Receptor | Main Ligand(s)/ Binding Partners |
Localization of the Interacting Residues on GPCR Structure | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Dopamine D3 Receptor (D3R) | ||||||||||||||||
| 3PBL [294] | Eticlopride (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: Asp110 (HB and SB); Val111 (HP) | TM4: - | ECL2: Ile183 (HP) | TM5: - | TM6: Phe345 (AR); Phe346 (HP); His349 (HB) | ECL3: - | TM7: - | |||||||
| Adenosine A2A receptor (A2AAR) | ||||||||||||||||
| 2YDO [240] |
Adeonosine (agonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: Phe168 (AR); Glu169 (HB) | TM5: - | TM6: Trp246 (HP); Leu249 (HP); Asn253 (HB) | ECL3: - | TM7: Ser277 (HB); H278 (2HB) | |||||||
| 2YDV [240] |
5′-(N-Ethylcarboxamido)adenosine (agonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: Val84 (HP); Val85 (HP); Thr88 (HB); | TM4: - | ECL2: Phe168 (AR); Glu169 (HB) | TM5: - | TM6: Trp246 (HP); Leu249 (HP); His250 (HB); Asn253 (2HB) | ECL3: - | TM7: Ser277 (HB); His278 (HB) | |||||||
| 3EML [44] | ZM241385 (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: Leu85 (AR) | TM4: - | ECL2: - | TM5: Met177 (HP) | TM6: Trp246 (HP); Leu249 (HP); His250 (AR); Asn253 (HB) | ECL3: His264 (AR) | TM7: Lys267 (HP); Met270 (HP) | |||||||
| 3PWH [241] | ZM241385 (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: Phe168 (AR) | TM5: Met177 (HP) | TM6: Leu249 (HP); His250 (AR); Asn253 (HB) | ECL3: - | TM7: Tyr271 (HP); Ile274 (HP) | |||||||
| 3QAK [43] | UK-432097 (agonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: Val84 (HP); Leu85 (HP) | TM4: - | ECL2: Phe168 (AR); Glu169 (2HB) | TM5: - | TM6: Trp246 (HP); Leu249 (HP); His250 (HB); Asn253 (HB) | ECL3: - | TM7: Met270 (HP); Tyr271 (HB and AR); Ile274 (HP); Ser277 (HB); His278 (2HB) | |||||||
| 3REY [241] | Xanthine amine congener (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: Phe168 (HP) | TM5: Met177 (HP) | TM6: Asn253 (HB) | ECL3: - | TM7: Met270 (HP); Ile274 (HP) | |||||||
| 3RFM [241] | Caffeine (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: Phe168 (HP) | TM5: - | TM6: - | ECL3: - | TM7: Ile274 (HP) | |||||||
| Receptor | Main Ligand(s)/ Binding Partners |
Localization of the Interacting Residues on GPCR Structure | ||||||||||||||
| Adenosine A2A Receptor (A2AAR) | ||||||||||||||||
| 3UZA [243] | 6-(2,6-Dimethylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: Phe168 (HP) | TM5: Met177 (HP) | TM6: Leu249 (HP); His250 (AR); Asn253 (2HB) | ECL3: - | TM7: Ile274 (HP) | |||||||
| 3UZC [243] |
4-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-2-chlorophenol (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: Val84 (HP); Leu85 (HP) | TM4: - | ECL2: Phe168 (AR) | TM5: Met177 (HP) | TM6: Trp246 (HP); Leu249 (HP); His250 (AR); Asn253 (2HB) | ECL3: - | TM7: Ile274 (HP); His278 (HB) | |||||||
| 3VG9 [242] |
ZM241385 (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: Leu85 (HP) | TM4: - | ECL2: Phe168 (HP) | TM5: - | TM6: Trp246 (HP); Leu249 (HP); His250 (AR); Asn253 (HB) | ECL3: - | TM7: Met270 (HP); Tyr271 (HP) | |||||||
| 3VGA [242] | ZM241385 (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: Leu85 (HP) | TM4: - | ECL2: Phe168 (AR) | TM5: Met177 (HP) | TM6: Leu249 (HP); His250 (AR) | ECL3: - | TM7: Met270 (HP) | |||||||
| 4EIY [244] | ZM241385 (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1:- | TM3: - | TM4: - | ECL2: Phe168 (AR); Glu169 (HB) | TM5: Met177 (HP) | TM6: Trp246 (HP); Leu249 (HP); His250 (AR); Asn253 (3HB) | ECL3: His264 (AR) | TM7: Leu267 (HP); Met270 (HP) | |||||||
| 4UG2 [245] | CGS21680 (agonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: Ser67 (HB) | ECL1: - | TM3: Val84 (HP); Leu85 (HP); Thr88 (HB) | TM4: - | ECL2: Phe168 (AR); Glu169 (HB) | TM5: - | TM6: Trp246 (HP); Leu249 (HP); His250 (HB); Asn253 (2HB) | ECL3: - | TM7: Met270 (HP); Ile274 (HP); Ser277 (HB); His278 (2HB) | |||||||
| 4UHR [245] | CGS21680 (agonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: Val84 (HP); Leu85 (HP); Thr88 (HB) | TM4: - | ECL2: Phe168 (AR) | TM5: - | TM6: Trp246 (HP); Leu249 (HP); His250 (HB); Asn253 (HB) | ECL3: - | TM7: Ile274 (HP); Ser277 (HB); His278 (2HB) | |||||||
| 5G53 [246] | 5′-(N-Ethylcarboxamido)adenosine (agonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: Val84 (HP); Leu85 (HP); Thr88 (HB) | TM4: - | ECL2: Phe168 (AR); Glu169 (HB) | TM5: - | TM6: Trp246 (HP); Leu249 (HP); His250 (HB); Asn253 (2HB) | ECL3: - | TM7: Ser277 (HB); His278 (2HB) | |||||||
| 5IU4 [247] | ZM241385 (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: Leu85 (HP) | TM4: - | ECL2: Phe168 (AR); Glu169 (HB) | TM5: Met177 (HP) | TM6: Trp246 (HP); Leu249 (HP); His250 (AR); Asn253 (3HB) | ECL3: His264 (AR) | TM7: Met270 (HP) | |||||||
| Receptor | Main Ligand(s)/ Binding Partners |
Localization of the Interacting Residues on GPCR Structure | ||||||||||||||
| Adenosine A2A Receptor (A2AAR) | ||||||||||||||||
| 5IU7 [247] | 2-(Furan-2-yl)-N5-(2-(4-phenylpiperidin-1-yl)ethyl)-1,2-dihydro-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: Leu85 (HP) | TM4: - | ECL2: Phe168 (AR); Glu169 (HB) | TM5: Met177 (HP) | TM6: Trp246 (HP); Leu249 (HP); His250 (AR); Asn253 (3HB) | ECL3: His264 (AR) | TM7: Met270 (HP) | |||||||
| 5IU8 [247] | 2-(Furan-2-yl)-N5-(2-(4-phenylpiperidin-1-yl)ethyl)-1,2-dihydro-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: Leu85 (HP) | TM4: - | ECL2: Phe168 (AR); Glu169 (HB) | TM5: Met177 (HP) | TM6: Trp246 (HP); Leu249 (HP); His250 (AR); Asn253 (2HB) | ECL3: - | TM7: Met270 (HP) | |||||||
| 5IUA [247] | 2-(Furan-2-yl)-N5-(3-(4-phenylpiperazin-1-yl)propyl)-1,2-dihydro-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: Leu85 (HP) | TM4: - | ECL2: Phe168 (AR); Glu169 (HB) | TM5: Met177 (HP) | TM6: Trp246 (HP); Leu249 (HP); His250 (AR); Asn253 (HB) | ECL3: - | TM7: Leu267 (HP); Met270 (HP) | |||||||
| 5IUB [247] | N5-(2-(4-(2,4-Difluorophenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-1,2-dihydro-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: Leu85 (HP) | TM4: - | ECL2: Phe168 (AR); Glu169 (HB) | TM5: Met177 (HP) | TM6: Trp246 (HP); Leu249 (HP); His250 (AR); Asn253 (3HB) | ECL3: His264 (AR); Ala265 | TM7: Leu267 (HB); Met270 (HP); Ile274 (HP) | |||||||
| 5K2A [249] | ZM241385 (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: Phe168 (AR); Glu169 (HB) | TM5: Met177 (HP) | TM6: Trp246 (HP); Leu249 (HP); His250 (AR); Asn253 (3HB) | ECL3: His264 (AR); Ala265 | TM7: Leu267 (HP); Met270 (HP) | |||||||
| 5K2B [249] | ZM241385 (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: Phe168 (AR); Glu169 (HB) | TM5: - | TM6: Trp246 (HP); Leu249 (HP); His250 (AR); Asn253 (3HB) | ECL3: - | TM7: Leu267 (HP); Met270 (HP) | |||||||
| 5K2C [249] | ZM241385 (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: Phe168 (AR); Glu169 (HB) | TM5: Met177 (HP) | TM6: Leu249 (HP); His250 (AR); Asn253 (3HB) | ECL3: His264 (AR) | TM7: Met270 (HP) | |||||||
| 5K2D [249] | ZM241385 (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: Phe168 (AR); Glu169 (HB) | TM5: Met177 (HP) | TM6: Leu249 (HP); His250 (AR); Asn253 (3HB) | ECL3: His264 (AR) | TM7: Met270 (HP) | |||||||
| 5UIG [252] | 5-Amino-N-[(2-methoxyphenyl)methyl]-2-(3-methylphenyl)-2H-1,2,3-triazole-4-carboximidamide (antagonist) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: Leu85 (HP) | TM4: - | ECL2: Phe168 (AR) | TM5: Met177 (HP) | TM6: Trp246 (HP); Leu249 (HP); His250 (AR) | ECL3: - | TM7: Tyr271 (HP); Ile274 (HP) | |||||||
| Receptor | Main Ligand(s)/ Binding Partners |
Localization of the Interacting Residues on GPCR Structure | ||||||||||||||
| Metabotropic Glutamate Receptor 2 (MGluR2) | ||||||||||||||||
| 5CNI [379] |
Glutamate (agonist) | Extracellular ATD: Arg57 (VdW); Arg61 (HB); Tyr144 (VdW); Ser145 (HB); Ala166 (HB); Ser167 (VdW); Thr168 (HB); Tyr216 (VdW); Asp295 (HB); Lys377 (VdW) | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: - | TM5: - | TM6: - | ECL3: - | TM7: - | |||||||
| 5CNJ [379] | LY2812223 (agonist) | Extracellular ATD: Arg57 (VdW); Arg61 (HB); Ser143 (VdW); Tyr144 (SB); Ser145 (HB); Ala166 (HB); Ser167 (VdW); Thr168 (HB); Tyr216 (VdW); Arg271 (VdW); Ser272 (VdW); Glu273 (VdW); Asp295 (HB); Gly296 (VdW); Lys377 (VdW) – chain A Arg57 (VdW); Arg61 (HB); Ser143 (VdW); Tyr144 (VdW); Ser145 (HB); Ala166 (VdW); Ser167 (VdW); Thr168 (HB); Tyr216 (VdW); Arg271 (VdW); Ser272 (VdW); Glu273 (VdW); Asp295 (HB); Gly296 (VdW); Lys377 (VdW) – chain B |
||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: - | TM5: - | TM6: - | ECL3: - | TM7: - | |||||||
| Metabotropic Glutamate Receptor 3 (MGluR3) | ||||||||||||||||
| 2E4U [380] | Glutamate (agonist) | Extracellular ATD: Arg64 (VdW); Arg68 (HB); Ser149 (VdW); Tyr150 (VdW); Ser151 (HB); Ala172 (VdW); Ser173 (VdW); Thr174 (HB); Tyr222 (VdW); Asp301 (HB); Lys389 (VdW) | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: - | TM5: - | TM6: - | ECL3: - | TM7: - | |||||||
| 2E4V [380] | DCG-IV (agonist) | Extracellular ATD: Arg64 (VdW); Arg68 (HB); Ser149 (VdW); Tyr150 (VdW); Ser151 (HB); Ala172 (VdW); Ser173 (VdW); Thr174 (HB); Tyr222 (VdW); Arg277 (VdW); Ser278 (HB); Asp301 (HB); Gly302 (VdW); Lys389 (VdW) | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: - | TM5: - | TM6: - | ECL3: - | TM7: - | |||||||
| 2E4W [380] | 1S,3S-ACPD (agonist) | Extracellular ATD: Arg64 (VdW); Arg68 (HB); Ser149 (VdW); Tyr150 (VdW); Ser151 (HB); Ala172 (HB); Ser173 (VdW); Thr174 (HB); Tyr222 (VdW); Asp301 (HB); Gly302 (VdW); Lys389 (VdW) | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: - | TM5: - | TM6: - | ECL3: - | TM7: - | |||||||
| 2E4X [380] | 1S,3R-ACPD (agonist) | Extracellular ATD: Arg64 (VdW); Arg68 (HB); Ser149 (VdW); Tyr150 (VdW); Ser151 (HB); Ala172 (HB); Ser173 (VdW); Thr174 (HB); Tyr222 (VdW); Asp301 (HB); Gly302 (VdW); Lys389 (VdW) | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: - | TM5: - | TM6: - | ECL3: - | TM7: - | |||||||
| 2E4Y [380] | 2R,4R-APDC (agonist) | Extracellular ATD: Arg64 (SB); Arg68 (HB); Ser149 (HB); Tyr150 (VdW); Ser151 (HB); Ala172 (HB); Ser173 (VdW); Thr174 (VdW); Tyr222 (VdW); Asp301 (HB) – chain A Arg64 (HB); Arg68 (HB); Tyr150 (VdW); Ser151 (HB); Ala172 (VdW); Ser173 (VdW); Thr174 (HB); Tyr222 (SB); Asp301 (HB); Gly302 (VdW); Lys389 (VdW) – chain B |
||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: - | TM5: - | TM6: - | ECL3: - | TM7: - | |||||||
| 5CNK [379] | Glutamate (agonist) | Extracellular ATD: Arg64 (VdW); Arg68 (HB); Ser149 (VdW); Tyr150 (VdW); Ser151 (HB); Ala172 (HB); Thr174 (VdW); Tyr222 (VdW); Asp301 (HB); Lys389 (HB) – chain A Arg64 (VdW); Arg68 (HB); Ser149 (VdW); Tyr150 (VdW); Ser151 (HB); Ala172 (HB); Thr174 (VdW); Tyr222 (VdW); Asp301 (HB); Lys389 (HB) – chain B |
||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: - | TM5: - | TM6: - | ECL3: - | TM7: - | |||||||
| 5CNM [379] | LY2812223 (agonist) | Extracellular ATD: Arg64 (VdW); Arg68 (HB); Tyr150 (VdW); Ser151 (HB); Ala172 (HB); Ser173 (VdW); Thr174 (VdW); Lys389 (HB) | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: - | TM4: - | ECL2: - | TM5: - | TM6: - | ECL3: - | TM7: - | |||||||
| Metabotropic Glutamate Receptor 5 (MGluR5) | ||||||||||||||||
| 4OO9 [381] | Mavoglurant (NAM) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: Ile625 (HP) | ECL1: - | TM3: Ile651 (HP); Pro655 (HP); Tyr659 (HP) |
TM4: Leu744 (HP); Asn747 (HB) | ECL2: - | TM5: - | TM6: - | ECL3: - | TM7: Ser805 (2HB); Val806 (HP); Ser809 (HB); Ala810 (HP) | |||||||
| 5CGC [382] | 3-Chloro-4-fluoro-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile (NAM) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: - | ECL1: - | TM3: Ile651 (HP); Pro655 (HP) | TM4: - | ECL2: - | TM5: Leu744 (HP) | TM6: Trp785 (AR); Phe788 (HP) | ECL3: - | TM7: Val806 (HP); Ser809 (HB); Ala810 (HP) | |||||||
| Receptor | Main Ligand(s)/ Binding Partners |
Localization of the Interacting Residues on GPCR Structure | ||||||||||||||
| Metabotropic Glutamate Receptor 5 (MGluR5) | ||||||||||||||||
| 5CGD [382] | HTL14242 (NAM) | Extracellular ATD: - | ||||||||||||||
| TM1: - | TM2: Ile625 (HP) | ECL1: - | TM3: Ile651 (HP); Pro655 (HP) | TM4: - | ECL2: - | TM5: Leu744 (HP) | TM6: Trp785 (HP); Phe788 (AR) | ECL3: - | TM7: Val806 (HP); Ser809 (HB) | |||||||
Among all the aforementioned GPCR-derived therapeutic targets of PD, the X-ray structure of five GPCRs (D3R, A2AAR, mGluR2, mGluR3, and mGluR5) has been determined in complex with small-molecule modulators. Relevant interactions were retrieved from the GPCRdb [575] and are divided into Hydrogen Bonds (HB), Salt Bridges (SB), HydroPhobic (HP), and ARomatic interactions (AR). For mGluR2 and mGluR3, the information related to ligand interaction was gathered using PDBeMOTIF [576], an online tool designed to analyse protein-ligand interaction by detecting Hydrogen Bonds (HB) and Van der Waals (VdW) interactions.