Demystifying the three dimensional structure of G protein-coupled receptors (GPCRs) with the aid of molecular modeling

2003 ◽  
pp. 2949 ◽  
Author(s):  
Stefano Moro ◽  
Francesca Deflorian ◽  
Giampiero Spalluto ◽  
Giorgia Pastorin ◽  
Barbara Cacciari ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
G Protein ◽  
Three Dimensional ◽  
G Protein Coupled Receptors ◽  
Dimensional Structure ◽  
Three Dimensional Structure ◽  
G Protein Coupled

scholarly journals Advances in Determination of a High-Resolution Three-Dimensional Structure of Rhodopsin, a Model of G-Protein-Coupled Receptors (GPCRs)†,‡

Biochemistry ◽  
2001 ◽  
Vol 40 (26) ◽  
pp. 7761-7772 ◽  
Author(s):  
David C. Teller ◽  
Tetsuji Okada ◽  
Craig A. Behnke ◽  
Krzysztof Palczewski ◽  
Ronald E. Stenkamp
Keyword(s):  
High Resolution ◽  
G Protein ◽  
Three Dimensional ◽  
G Protein Coupled Receptors ◽  
Dimensional Structure ◽  
Three Dimensional Structure ◽  
G Protein Coupled

Modulation of proteostasis and protein trafficking: a therapeutic avenue for misfolded G protein-coupled receptors causing disease in humans

2019 ◽  
Vol 3 (1) ◽  
pp. 39-52
Author(s):  
Alfredo Ulloa-Aguirre ◽  
Jo Ann Janovick
Keyword(s):  
G Protein ◽  
Protein Trafficking ◽  
Protein Misfolding ◽  
Hypogonadotropic Hypogonadism ◽  
Three Dimensional ◽  
G Protein Coupled Receptors ◽  
Dimensional Structure ◽  
Stable Conformation ◽  
Mutant Proteins ◽  
G Protein Coupled

Abstract Proteostasis refers to the process whereby the cell maintains in equilibrium the protein content of different compartments. This system consists of a highly interconnected network intended to efficiently regulate the synthesis, folding, trafficking, and degradation of newly synthesized proteins. Molecular chaperones are key players of the proteostasis network. These proteins assist in the assembly and folding processes of newly synthesized proteins in a concerted manner to achieve a three-dimensional structure compatible with export from the endoplasmic reticulum to other cell compartments. Pharmacologic interventions intended to modulate the proteostasis network and tackle the devastating effects of conformational diseases caused by protein misfolding are under development. These include small molecules called pharmacoperones, which are highly specific toward the target protein serving as a molecular framework to cause misfolded mutant proteins to fold and adopt a stable conformation suitable for passing the scrutiny of the quality control system and reach its correct location within the cell. Here, we review the main components of the proteostasis network and how pharmacoperones may be employed to correct misfolding of two G protein-coupled receptors, the vasopressin 2 receptor and the gonadotropin-releasing hormone receptor, whose mutations lead to X-linked nephrogenic diabetes insipidus and congenital hypogonadotropic hypogonadism in humans respectively.

Polypharmacology – a challenge for current drug design approaches

2019 ◽  
Vol 6 (3) ◽  
pp. 19-23
Author(s):  
Sabina Podlewska ◽  
Rafał Kurczab
Keyword(s):  
Molecular Modeling ◽  
Side Effects ◽  
Drug Design ◽  
G Protein ◽  
Design Process ◽  
Serotonin Receptors ◽  
G Protein Coupled Receptors ◽  
Activity Profile ◽  
Activity Groups ◽  
G Protein Coupled

Drug design process faces many challenges, and the most important ones are connected with side effects. Finding compounds that possess affinity towards target of interest is relatively simple; however, an approach one disease-one target is now making space for the search of polypharmacological ligands, where activity towards several proteins is considered at one time. Such proteins are not always the target ones, but very often such panels include also anti-targets, interaction with which is not desired, due to the side effects that may occur upon such contact. In the study, we examined ligands of four G protein-coupled receptors, forming antipsychotic profile: dopamine receptor D2, serotonin receptors 5-HT2A, 5-HT2C (anti-target), and 5-HT6. Number of ligands belonging to particular activity groups, as well as the selected compound structures are examined in detail. Also compound similarity between sets of different activity groups is analysed, giving a picture of difficulty of constructing molecular modeling methodologies that can help in the search of compounds with desired activity profile.

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