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.…”

Energetic factors determining the binding of type I inhibitors to c-Met kinase: experimental studies and quantum mechanical calculations

“…Because the fused aromatic rings in the present study are difficult to decompose into local electrostatic contributions, it remains to be determined whether the local direct model is suitable for such systems. The sulfur-π interaction occurs less commonly in proteinligand systems than does the well-known π-π interaction [39][40][41] . Met-1211 interacts with the inhibitors described in this study, which may provide some clues about the nature of this type of interaction.…”

An Unaltered Orthosteric Site and a Network of Long-Range Allosteric Interactions for PNU-120596 in α7 Nicotinic Acetylcholine Receptors

“…In this analysis, the first perturbation is mutation of the protein (with conventional or non-canonical amino acids); and the second perturbation is not a mutation, but the addition of PNU-120596. Non-additivity of the two perturbations indicates that the protein mutation differentially impacts receptor function depending on whether PNU-120596 is or is not present, suggesting that the residue under study plays an important role in allosteric modulation (Daeffler, et al, 2012; Gleitsman, et al, 2009; Miles, et al, 2012). The analysis parallels that of the common double mutant cycle analysis, including the notion of an interaction energy, designated as ΔΔG.…”