Functionally Important Aromatic–Aromatic and Sulfur−π Interactions in the D2 Dopamine Receptor

Abstract

The recently published crystal structure of the D3 dopamine receptor shows a tightly packed region of aromatic residues on helices 5 and 6 in the space bridging the binding site and what is thought to be the origin of intracellular helical motion. This highly conserved region also makes contacts with residues on helix 3, and here we use double mutant cycle analysis and unnatural amino acid mutagenesis to probe the functional role of several residues in this region of the closely related D2 dopamine receptor. Of the eight mutant pairs examined, all show significant functional coupling (Ω > 2), with the largest coupling coefficients observed between residues on different helices, C3.36/W6.48, T3.37/S5.46 and F5.47/F6.52. Additionally, three aromatic residues examined, F5.47, Y5.48, and F5.51 show consistent trends upon progressive fluorination of the aromatic side chain. These trends are indicative of a functionally important electrostatic interaction with the face of the aromatic residue examined, which is likely attributed to aromatic-aromatic interactions between residues in this microdomain. We also propose that the previously determined fluorination trend at W6.48 is likely due to a sulfur-π interaction with the side chain of C3.36. We conclude that these residues form a tightly packed structural microdomain that connects helices 3, 5, and 6, thus forming a barrier that prevents dopamine from binding further toward the intracellular surface. Upon activation, these residues likely do not change their relative conformation, but rather act to translate agonist binding at the extracellular surface into the large intracellular movements that characterize receptor activation.

Synthesis, antibacterial activities and phospholipid membrane interactions of novel dialkyl 2,2’-disulfanediyldibenzoates

“…This class of interaction is well known and is significant in biomolecular systems, responsible for stabilising the folding of proteins and the associated quaternary structures. [23,24]. The distance between the centroid of the C36-C37-C17-C16-C35-C38 phenyl ring and S2 measures 3.765(1) Å [23].…”

Modulation of indole ring annulation in ergoline template: chemistry, receptor binding and in vivo pharmacology with 6-OHDA model of Parkinson’s disease

“…The allylic conjugation in compound 19 through p bond may provide stabilization at D2-like receptor leading to increase in selectivity (Ross et al, 1986). It was observed that the introduction of p interaction remarkably increases selectivity toward D2-like receptor without significantly affecting affinity (Daeffler et al, 2012). Presumably, the N-allyl group may regulate the selectivity for D2-like receptor (Ross et al, 1986), because N-allyl group is flexible and can rotate among several conformations (Feinberg et al, 1976).…”

Dibenzosuberyl substituted polyamines and analogs of clomipramine as effective inhibitors of trypanothione reductase; molecular docking, and assessment of trypanocidal activities

“…At BR 4, the DBS group is oriented with one aryl group involved in a sulfur-π interaction with Met114. [104][105][106] The DBS group is also located close to Trp22 with the π-faces of the aryl groups at an approximate 30-40 o angle from parallel. This site also has hydrophobic regions from Met114 and Leu18 that interact with the DBS.…”