scholarly journals Ab Initio Modelling the Structure of Proton-Sensing G-Protein Coupled Receptor GPR151

2020 ◽  
Author(s):  
Wei Li
Keyword(s):  
Ab Initio ◽  
G Protein ◽  
Protein Function ◽  
Protein Structures ◽  
Three Dimensional ◽  
Data Bank ◽  
Dimensional Structure ◽  
G Protein Coupled Receptor ◽  
Great Excess ◽  
G Protein Coupled

Protein is the proteios building block of life. Evolutionarily, its sequence is not as conserved as its structure, making it more reasonable for protein structure, instead of protein sequence, to be the descriptor of protein function. Yet, in the National Center for Biotechnology Information (NCBI) database, the number of experimentally identified protein sequences is in great excess of that of experimentally determined protein structures inside the almost-half-a-century old Protein Data Bank (PDB). For instance, GPR151 is an proton-sensing G-protein coupled receptor (GPCR) originally identified as homologous to galanin receptors. As of March 19, 2020, GPR151’s structure has not been experimentally determined and deposited in PDB yet. Thus, an ab initio modelling approach was employed here to build a three-dimensional structure of GPR151. Overall, the ab initio GPR151 model presented herein constitutes the first structural hypothesis of GPR151 to be experimentally tested in future with previously published, currently ongoing and future GPR151 studies.

scholarly journals Structural Characterization of Receptor–Receptor Interactions in the Allosteric Modulation of G Protein-Coupled Receptor (GPCR) Dimers

2021 ◽  
Vol 22 (6) ◽  
pp. 3241
Author(s):  
Raudah Lazim ◽  
Donghyuk Suh ◽  
Jai Woo Lee ◽  
Thi Ngoc Lan Vu ◽  
Sanghee Yoon ◽  
...  
Keyword(s):  
G Protein ◽  
Protein Interactions ◽  
Metabotropic Glutamate Receptor ◽  
Three Dimensional ◽  
Allosteric Modulation ◽  
Experimental Investigations ◽  
G Protein Coupled Receptor ◽  
Metabotropic Glutamate ◽  
Gpcr Activation ◽  
G Protein Coupled

G protein-coupled receptor (GPCR) oligomerization, while contentious, continues to attract the attention of researchers. Numerous experimental investigations have validated the presence of GPCR dimers, and the relevance of dimerization in the effectuation of physiological functions intensifies the attractiveness of this concept as a potential therapeutic target. GPCRs, as a single entity, have been the main source of scrutiny for drug design objectives for multiple diseases such as cancer, inflammation, cardiac, and respiratory diseases. The existence of dimers broadens the research scope of GPCR functions, revealing new signaling pathways that can be targeted for disease pathogenesis that have not previously been reported when GPCRs were only viewed in their monomeric form. This review will highlight several aspects of GPCR dimerization, which include a summary of the structural elucidation of the allosteric modulation of class C GPCR activation offered through recent solutions to the three-dimensional, full-length structures of metabotropic glutamate receptor and γ-aminobutyric acid B receptor as well as the role of dimerization in the modification of GPCR function and allostery. With the growing influence of computational methods in the study of GPCRs, we will also be reviewing recent computational tools that have been utilized to map protein–protein interactions (PPI).

MRPC (Missing Regions in Polypeptide Chains): a knowledgebase

2019 ◽  
Vol 52 (6) ◽  
pp. 1422-1426
Author(s):  
Rajendran Santhosh ◽  
Namrata Bankoti ◽  
Adgonda Malgonnavar Padmashri ◽  
Daliah Michael ◽  
Jeyaraman Jeyakanthan ◽  
...  
Keyword(s):  
Protein Structures ◽  
Three Dimensional ◽  
Protein Molecule ◽  
Data Bank ◽  
Protein Crystal ◽  
Dimensional Structure ◽  
Protein Structure Analysis ◽  
Three Dimensional Structure ◽  
X Ray Crystallography ◽  
Polypeptide Chains

Missing regions in protein crystal structures are those regions that cannot be resolved, mainly owing to poor electron density (if the three-dimensional structure was solved using X-ray crystallography). These missing regions are known to have high B factors and could represent loops with a possibility of being part of an active site of the protein molecule. Thus, they are likely to provide valuable information and play a crucial role in the design of inhibitors and drugs and in protein structure analysis. In view of this, an online database, Missing Regions in Polypeptide Chains (MRPC), has been developed which provides information about the missing regions in protein structures available in the Protein Data Bank. In addition, the new database has an option for users to obtain the above data for non-homologous protein structures (25 and 90%). A user-friendly graphical interface with various options has been incorporated, with a provision to view the three-dimensional structure of the protein along with the missing regions using JSmol. The MRPC database is updated regularly (currently once every three months) and can be accessed freely at the URL http://cluster.physics.iisc.ac.in/mrpc.

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.

scholarly journals Mechanism of β-arrestin recruitment by the μ-opioid G protein-coupled receptor

2020 ◽  
Vol 117 (28) ◽  
pp. 16346-16355 ◽  
Author(s):  
Amirhossein Mafi ◽  
Soo-Kyung Kim ◽  
William A. Goddard
Keyword(s):  
Side Effects ◽  
G Protein ◽  
Three Dimensional ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
G Protein Coupled Receptor ◽  
Intracellular Loop ◽  
Cytoplasmic Region ◽  
Gi Protein ◽  
G Protein Coupled

Agonists to the μ-opioid G protein-coupled receptor (μOR) can alleviate pain through activation of G protein signaling, but they can also induce β-arrestin activation, leading to such side effects as respiratory depression. Biased ligands to μOR that induce G protein signaling without inducing β-arrestin signaling can alleviate pain while reducing side effects. However, the mechanism for stimulating β-arrestin signaling is not known, making it difficult to design optimum biased ligands. We use extensive molecular dynamics simulations to determine three-dimensional (3D) structures of activated β-arrestin2 stabilized by phosphorylated μOR bound to the morphine and D-Ala2,N-MePhe4, Gly-ol]-enkephalin (DAMGO) nonbiased agonists and to the TRV130 biased agonist. For nonbiased agonists, we find that the β-arrestin2 couples to the phosphorylated μOR by forming strong polar interactions with intracellular loop 2 (ICL2) and either the ICL3 or cytoplasmic region of transmembrane (TM6). Strikingly, Gi protein makes identical strong bonds with these same ICLs. Thus, the Gi protein and β-arrestin2 compete for the same binding site even though their recruitment leads to much different outcomes. On the other hand, we find that TRV130 has a greater tendency to bind the extracellular portion of TM2 and TM3, which repositions TM6 in the cytoplasmic region of μOR, hindering β-arrestin2 from making polar anchors to the ICL3 or to the cytosolic end of TM6. This dramatically reduces the affinity between μOR and β-arrestin2.

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

TOP: a new method for protein structure comparisons and similarity searches

2000 ◽  
Vol 33 (1) ◽  
pp. 176-183 ◽  
Author(s):  
Guoguang Lu
Keyword(s):  
User Interface ◽  
Protein Structure ◽  
Protein Structures ◽  
Three Dimensional ◽  
Data Bank ◽  
Structure Alignment ◽  
Dimensional Structure ◽  
Protein Structure Alignment ◽  
Protein Structure Analysis ◽  
Structure Comparison

In order to facilitate the three-dimensional structure comparison of proteins, software for making comparisons and searching for similarities to protein structures in databases has been developed. The program identifies the residues that share similar positions of both main-chain and side-chain atoms between two proteins. The unique functions of the software also include database processingviaInternet- and Web-based servers for different types of users. The developed method and its friendly user interface copes with many of the problems that frequently occur in protein structure comparisons, such as detecting structurally equivalent residues, misalignment caused by coincident match of Cαatoms, circular sequence permutations, tedious repetition of access, maintenance of the most recent database, and inconvenience of user interface. The program is also designed to cooperate with other tools in structural bioinformatics, such as the 3DB Browser software [Prilusky (1998).Protein Data Bank Q. Newslett.84, 3–4] and the SCOP database [Murzin, Brenner, Hubbard & Chothia (1995).J. Mol. Biol.247, 536–540], for convenient molecular modelling and protein structure analysis. A similarity ranking score of `structure diversity' is proposed in order to estimate the evolutionary distance between proteins based on the comparisons of their three-dimensional structures. The function of the program has been utilized as a part of an automated program for multiple protein structure alignment. In this paper, the algorithm of the program and results of systematic tests are presented and discussed.

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
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