scholarly journals Structure of the human gonadotropin-releasing hormone receptor GnRH1R reveals an unusual ligand binding mode

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Wei Yan ◽  
Lin Cheng ◽  
Wei Wang ◽  
Chao Wu ◽  
Xin Yang ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Reproductive Function ◽  
Binding Mode ◽  
Structural Features ◽  
Docking Studies ◽  
Rational Drug Design ◽  
Releasing Hormone ◽  
Promising Therapeutic Target ◽  
Rational Drug ◽  
Main Regulator

Abstract Gonadotrophin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone, is the main regulator of the reproductive system, acting on gonadotropic cells by binding to the GnRH1 receptor (GnRH1R). The GnRH-GnRH1R system is a promising therapeutic target for maintaining reproductive function; to date, a number of ligands targeting GnRH1R for disease treatment are available on the market. Here, we report the crystal structure of GnRH1R bound to the small-molecule drug elagolix at 2.8 Å resolution. The structure reveals an interesting N-terminus that could co-occupy the enlarged orthosteric binding site together with elagolix. The unusual ligand binding mode was further investigated by structural analyses, functional assays and molecular docking studies. On the other hand, because of the unique characteristic of lacking a cytoplasmic C-terminal helix, GnRH1R exhibits different microswitch structural features from other class A GPCRs. In summary, this study provides insight into the ligand binding mode of GnRH1R and offers an atomic framework for rational drug design.

scholarly journals Mechanism of ligand recognition by human ACE2 receptor

2020 ◽  
Author(s):  
Apurba Bhattarai ◽  
Shristi Pawnikar ◽  
Yinglong Miao
Keyword(s):  
Ligand Binding ◽  
Renin Angiotensin System ◽  
Rational Drug Design ◽  
Renal Diseases ◽  
Ligand Recognition ◽  
Conformational Ensemble ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Accelerated Molecular Dynamics ◽  
Rational Drug

AbstractAngiotensin converting enzyme 2 (ACE2) plays a key role in renin-angiotensin system regulation and amino acid homeostasis. Human ACE2 acts as the receptor for severe acute respiratory syndrome coronaviruses SARS-CoV and SARS-CoV-2. ACE2 is also widely expressed in epithelial cells of lungs, heart, kidney and pancreas. It is considered an important drug target for treating SARS-CoV-2, as well as pulmonary diseases, heart failure, hypertension, renal diseases and diabetes. Despite the critical importance, the mechanism of ligand binding to the human ACE2 receptor remains unknown. Here, we address this challenge through all-atom simulations using a novel ligand Gaussian accelerated molecular dynamics (LiGaMD) method. Microsecond LiGaMD simulations have successfully captured both binding and unbinding of the MLN-4760 inhibitor in the ACE2 receptor. In the ligand unbound state, the ACE2 receptor samples distinct Open, Partially Open and Closed conformations. Ligand binding biases the receptor conformational ensemble towards the Closed state. The LiGaMD simulations thus suggest a conformational selection mechanism for ligand recognition by the ACE2 receptor. Our simulation findings are expected to facilitate rational drug design of ACE2 against coronaviruses and other related human diseases.

Nicotinic acetylcholine receptors: α-conotoxins as templates for rational drug design

2003 ◽  
Vol 31 (3) ◽  
pp. 634-636 ◽  
Author(s):  
Robert W. Janes
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Structural Features ◽  
Docking Studies ◽  
Rational Drug Design ◽  
Synaptic Membranes ◽  
Nicotinic Acetylcholine ◽  
Computational Docking ◽  
Acetylcholine Binding Protein ◽  
Topological Features

Nicotinic acetylcholine receptors (nAChRs) mediate the passage of potassium and sodium ions across synaptic membranes. Two classes of receptors exist: the neuromuscular nAChRs, which mediate signals between nerve and muscle cells, and the neuronal nAChRs, which are found throughout the nervous system. For treatment of diseases involving nAChRs, drugs must be designed with a high level of selectivity towards only one of these classes or subclasses (in the case of neuronal receptors). α-Conotoxins, small polypeptides isolated from the venoms of marine snails, represent molecules with just this type of selectivity, with specificity even towards certain subclasses of nAChRs. The availability of high-resolution crystal structures of α-conotoxins provides the opportunity to examine the structural features that orchestrate their preferential blocking action. In the present study of a neuromuscular- and a neuronal-specific α-conotoxin, SI and EpI respectively, important and significant differences can be seen in the shapes of the molecules, which must reflect topological features of the different types of target receptor subunits. These then provide a template for computational docking studies with the homologous acetylcholine-binding protein, whose structure is known, so drug analogues of the naturally occurring toxins can be developed with the desired specificities.

Docking studies and model development of tea polyphenol proteasome inhibitors: Applications to rational drug design

2003 ◽  
Vol 54 (1) ◽  
pp. 58-70 ◽  
Author(s):  
David M. Smith ◽  
Kenyon G. Daniel ◽  
Zhigang Wang ◽  
Wayne C. Guida ◽  
Tak-Hang Chan ◽  
...  
Keyword(s):  
Drug Design ◽  
Model Development ◽  
Proteasome Inhibitors ◽  
Docking Studies ◽  
Rational Drug Design ◽  
Tea Polyphenol ◽  
Rational Drug

scholarly journals Computational molecular modelling as a platform for a deeper understanding of protein dynamics and rational drug design

2020 ◽  
Author(s):  
Gianvito Grasso ◽  
Lorenzo Pallante ◽  
Jack A. Tuszynski ◽  
Umberto Morbiducci ◽  
Marco A. Deriu
Keyword(s):  
Molecular Modelling ◽  
Molecular Level ◽  
Structural Features ◽  
Rational Drug Design ◽  
Therapeutic Approaches ◽  
Amyloidogenic Proteins ◽  
Rational Drug ◽  
Aggregation Inhibitors ◽  
The Stability ◽  
Toxicity Pathways

Elucidating structural features of protein aggregation at molecular level may provide novel opportunities for overarching therapeutic approaches such as blocking common aggregation-induced cellular toxicity pathways. In this context molecular modelling stimulates further research on amyloid aggregation modulators and modelling platforms can be used to test the efficiency of potential aggregation inhibitors aimed at destabilizing/reducing the stability of the amyloidogenic proteins

Cyclin Dependent Kinase as a Novel Therapeutic Target: An Endless Story

2020 ◽  
Vol 14 ◽  
Author(s):  
Ahmed Mohamed Etman ◽  
Sherif Sabry Abdel Mageed ◽  
Mohamed Ahmed Ali ◽  
Mahmoud Abd El Monem El Hassab
Keyword(s):  
Molecular Mechanisms ◽  
Binding Pocket ◽  
Structural Features ◽  
Rational Drug Design ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinases ◽  
Therapeutic Class ◽  
Pharmacological Targets ◽  
Rational Drug ◽  
Cycle Regulation

Abstract:: Cyclin Dependent Kinases (CDKs) are a family of enzymes that along with their Cyclin partners play a crucial role in cell cycle regulation at many biological functions such as proliferation, differentiation, DNA repair and apoptosis. Thus, they are tightly regulated by a vast of inhibitory and activating enzymes. Deregulation of these kinases’ activity either by amplification, overexpression or mutation of CDKs or Cyclins leads to uncontrolled proliferation of cancer cells. Hyperactivity of these kinases has been reported in wide variety of human cancers. Hence, CDKs has been established as one of the most attractive pharmacological targets in the development of promising anticancer drugs. The elucidated structural features and the well characterized molecular mechanisms of CDKs have been the guide in designing inhibitors to these kinases. Yet they remain a challenging therapeutic class as they share conserved structure similarity in their active site. Several inhibitors have been discovered from natural sources or identified through high through put screening and rational drug design approaches. Most of these inhibitors target the ATP binding pocket, so they suffer from many limitations. Now a growing number of ATP non-competitive peptides and small molecules have been reported.

scholarly journals Molecular Modeling Studies on the Binding Mode of the PD-1/PD-L1 Complex Inhibitors

2019 ◽  
Vol 20 (18) ◽  
pp. 4654
Author(s):  
Suliman Almahmoud ◽  
Haizhen A. Zhong
Keyword(s):  
Cell Death ◽  
Molecular Docking ◽  
Programmed Cell Death ◽  
Ligand Binding ◽  
Binding Mode ◽  
Docking Studies ◽  
Important Target ◽  
Molecular Modeling Studies ◽  
L1 Protein ◽  
Cell Death Protein

The programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) is an immune checkpoint (ICP) overexpressed in various types of tumors; thus, it has been considered as an important target for cancer therapy. To determine important residues for ligand binding, we applied molecular docking studies to PD-1/PD-L1 complex inhibitors against the PD-L1 protein. Our data revealed that the residues Tyr56, Asp122, and Lys124 play critical roles in ligand binding to the PD-L1 protein and they could be used to design ligands that are active against the PD-1/PD-L1 complex. The formation of H-bonds with Arg125 of the PD-L1 protein may enhance the potency of the PD-1/PD-L1 binding.

scholarly journals Restriction of S-adenosylmethionine conformational freedom by knotted protein binding sites

2019 ◽  
Author(s):  
Agata P. Perlinska ◽  
Adam Stasiulewicz ◽  
Ewa K. Nawrocka ◽  
Krzysztof Kazimierczuk ◽  
Piotr Setny ◽  
...  
Keyword(s):  
Binding Sites ◽  
Protein Function ◽  
Tight Binding ◽  
Structural Features ◽  
Rational Drug Design ◽  
Conformational Space ◽  
Nmr Studies ◽  
Rational Drug ◽  
Specific Proteins ◽  
Conformational Freedom

AbstractS-adenosylmethionine (SAM) is one of the most important enzyme substrates. It is vital for the function of various proteins, including large group of methyltransferases (MTs). Intriguingly, some bacterial and eukaryotic MTs, while catalysing the same reaction, possess significantly different topologies, with the former being a knotted one. Here, we conducted a comprehensive analysis of SAM conformational space and factors that affect its vastness. We investigated SAM in two forms: free in water (via NMR studies and explicit solvent simulations) and bound to proteins (based on all data available in the PDB). We identified structural descriptors – angles which show the major differences in SAM conformation between unknotted and knotted methyltransferases. Moreover, we report that this is caused mainly by a characteristic for knotted MTs tight binding site formed by the knot and the presence of adenine-binding loop. Additionally, we elucidate conformational restrictions imposed on SAM molecules by other protein groups in comparison to conformational space in water.Author summaryThe topology of a folded polypeptide chain has great impact on the resulting protein function and its interaction with ligands. Interestingly, topological constraints appear to affect binding of one of the most ubiquitous substrates in the cell, S-adenosylmethionine (SAM), to its target proteins. Here, we demonstrate how binding sites of specific proteins restrict SAM conformational freedom in comparison to its unbound state, with a special interest in proteins with non-trivial topology, including an exciting group of knotted methyltransferases. Using a vast array of computational methods combined with NMR experiments, we identify key structural features of knotted methyltransferases that impose unorthodox SAM conformations. We compare them with the characteristics of standard, unknotted SAM binding proteins. These results are significant for understanding differences between analogous, yet topologically different enzymes, as well as for future rational drug design.

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