scholarly journals Exposing structural variations in SARS-CoV-2 evolution

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jiaan Yang ◽  
Peng Zhang ◽  
Wen Xiang Cheng ◽  
Youyong Lu ◽  
Wu Gang ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Critical Role ◽  
Protein Sequences ◽  
Virus Evolution ◽  
Structure And Function ◽  
Structural Variations ◽  
Physiochemical Properties ◽  
Variant Lineage ◽  
Alpha Variant ◽  
And Function

AbstractThe mutation of SARS-CoV-2 influences viral function as residue replacements affect both physiochemical properties and folding conformations. Although a large amount of data on SARS-CoV-2 is available, the investigation of how viral functions change in response to mutations is hampered by a lack of effective structural analysis. Here, we exploit the advances of protein structure fingerprint technology to study the folding conformational changes induced by mutations. With integration of both protein sequences and folding conformations, the structures are aligned for SARS-CoV to SARS-CoV-2, including Alpha variant (lineage B.1.1.7) and Delta variant (lineage B.1.617.2). The results showed that the virus evolution with change in mutational positions and physicochemical properties increased the affinity between spike protein and ACE2, which plays a critical role in coronavirus entry into human cells. Additionally, these structural variations impact vaccine effectiveness and drug function over the course of SARS-CoV-2 evolution. The analysis of structural variations revealed how the coronavirus has gradually evolved in both structure and function and how the SARS-CoV-2 variants have contributed to more severe acute disease worldwide.

scholarly journals Exposing Structural Variations in SARS-CoV-2 Evolution

2021 ◽  
Author(s):  
Jiaan Yang ◽  
Peng Zhang ◽  
Wen Xiang Cheng ◽  
Youyong Lu ◽  
Wu Gang ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Critical Role ◽  
Protein Sequences ◽  
Structure And Function ◽  
Spike Protein ◽  
Structural Variations ◽  
Physiochemical Properties ◽  
Binding Interface ◽  
The Uk ◽  
And Function

Abstract The mutation of SARS-CoV-2 influences viral function as residue replacements affect both physiochemical properties and folding conformations. Although a large amount of data on SARS-CoV-2 is available, the investigation of how viral functions change in response to mutations is hampered by a lack of effective structural analysis. Here, we exploit advances in protein structure fingerprint technology to study the folding conformational changes induced by mutations. With the integration of both protein sequences and folding conformations and alignments of SARS-CoV to SARS-CoV-2, the UK variant and India variant, we found that structural variations in the spike protein at the binding interface interacting with ACE2 play a critical role in coronavirus entry into human cells. Additionally, the structural variations impact vaccine effectiveness and drug function over the course of SARS-CoV-2 evolution. The analysis of structural variations revealed how the coronavirus has gradually evolved in both structure and function and how the SARS-CoV-2 variants have contributed to more severe acute disease worldwide.

The Laryngeal Epithelium in Reflux

2011 ◽  
Vol 21 (3) ◽  
pp. 112-117 ◽  
Author(s):  
Elizabeth Erickson-Levendoski ◽  
Mahalakshmi Sivasankar
Keyword(s):  
Laryngopharyngeal Reflux ◽  
Critical Role ◽  
Structure And Function ◽  
Laryngeal Disease ◽  
Health And Disease ◽  
And Function ◽  
The Impact

The epithelium plays a critical role in the maintenance of laryngeal health. This is evident in that laryngeal disease may result when the integrity of the epithelium is compromised by insults such as laryngopharyngeal reflux. In this article, we will review the structure and function of the laryngeal epithelium and summarize the impact of laryngopharyngeal reflux on the epithelium. Research investigating the ramifications of reflux on the epithelium has improved our understanding of laryngeal disease associated with laryngopharyngeal reflux. It further highlights the need for continued research on the laryngeal epithelium in health and disease.

scholarly journals The contribution of voltage clamp fluorometry to the understanding of channel and transporter mechanisms

2019 ◽  
Vol 151 (10) ◽  
pp. 1163-1172 ◽  
Author(s):  
John Cowgill ◽  
Baron Chanda
Keyword(s):  
Voltage Clamp ◽  
Conformational Changes ◽  
Physiological State ◽  
Structure And Function ◽  
Modern Biology ◽  
The Past ◽  
Mechanistic Insight ◽  
Atomistic Models ◽  
Multiple Conformations ◽  
And Function

Key advances in single particle cryo-EM methods in the past decade have ushered in a resolution revolution in modern biology. The structures of many ion channels and transporters that were previously recalcitrant to crystallography have now been solved. Yet, despite having atomistic models of many complexes, some in multiple conformations, it has been challenging to glean mechanistic insight from these structures. To some extent this reflects our inability to unambiguously assign a given structure to a particular physiological state. One approach that may allow us to bridge this gap between structure and function is voltage clamp fluorometry (VCF). Using this technique, dynamic conformational changes can be measured while simultaneously monitoring the functional state of the channel or transporter. Many of the important papers that have used VCF to probe the gating mechanisms of channels and transporters have been published in the Journal of General Physiology. In this review, we provide an overview of the development of VCF and discuss some of the key problems that have been addressed using this approach. We end with a brief discussion of the outlook for this technique in the era of high-resolution structures.

Critical Role of Zinc Ion on E. coli Glutamyl-Queuosine-tRNAAsp Synthetase (Glu-Q-RS) Structure and Function

2014 ◽  
Vol 33 (2) ◽  
pp. 143-149 ◽  
Author(s):  
Sutapa Ray ◽  
Victor Banerjee ◽  
Mickael Blaise ◽  
Baisakhi Banerjee ◽  
Kali Pada Das ◽  
...  
Keyword(s):  
Critical Role ◽  
Zinc Ion ◽  
Structure And Function ◽  
E Coli ◽  
And Function

scholarly journals Review on various factors responsible for neurodegenerative disorders

2021 ◽  
Vol 16 (1) ◽  
pp. 126-132
Author(s):  
Harshwardhan J Tembhurnikar ◽  
Neha D Thool ◽  
Rasika J Patil ◽  
Ranjita K Das
Keyword(s):  
Oxidative Stress ◽  
Nervous System ◽  
Neurodegenerative Disorders ◽  
Protein Misfolding ◽  
Critical Role ◽  
Structure And Function ◽  
Neuronal Structure ◽  
Pathophysiological Mechanisms ◽  
Neurological Illnesses ◽  
And Function

Neurodegenerative disorders are nervous system disorders that result in the loss of neuronal structure and function. As shown in Alzheimer's and Parkinson's disease, these changes cause a loss of various capacities, including cognition and mobility. Several factors have been discovered to play a critical role in the etiology of common neurological illnesses, including oxidative stress and protein misfolding. It's still unclear if these factors cause or contribute to the progression of the illnesses. Despite efforts to understand the molecular and pathophysiological mechanisms behind these pathways, many aspects remain unknown. The goal of this review is to investigate the numerous factors linked to neurodegeneration.

scholarly journals Current understanding of thalamic structure and function in migraine

Cephalalgia ◽  
2018 ◽  
Vol 39 (13) ◽  
pp. 1675-1682 ◽  
Author(s):  
Samaira Younis ◽  
Anders Hougaard ◽  
Rodrigo Noseda ◽  
Messoud Ashina
Keyword(s):  
Drug Target ◽  
Critical Role ◽  
Structure And Function ◽  
Pain Modulation ◽  
Clinical Implications ◽  
Important Position ◽  
Cortical Regions ◽  
And Function ◽  
Thalamic Structure

Objective To review and discuss the literature on the role of thalamic structure and function in migraine. Discussion The thalamus holds an important position in our understanding of allodynia, central sensitization and photophobia in migraine. Structural and functional findings suggest abnormal functional connectivity between the thalamus and various cortical regions pointing towards an altered pain processing in migraine. Pharmacological nociceptive modulation suggests that the thalamus is a potential drug target. Conclusion A critical role for the thalamus in migraine-related allodynia and photophobia is well established. Additionally, the thalamus is most likely involved in the dysfunctional pain modulation and processing in migraine, but further research is needed to clarify the exact clinical implications of these findings.

Nanoscale Analysis of the Effect of Pathogenic Mutations on Polycystin-1

2010 ◽  
Author(s):  
Liang Ma ◽  
Meixiang Xu ◽  
Andres F. Oberhauser
Keyword(s):  
Single Molecule ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Structure And Function ◽  
Eukaryotic Cells ◽  
Mechanical Forces ◽  
Force Microscopy ◽  
Physiological Conditions ◽  
Atomic Force ◽  
And Function

The activity of proteins and their complexes often involves the conversion of chemical energy (stored or supplied) into mechanical work through conformational changes. Mechanical forces are also crucial for the regulation of the structure and function of cells and tissues. Thus, the shape of eukaryotic cells is the result of cycles of mechano-sensing, mechano-transduction, and mechano-response. Recently developed single-molecule atomic force microscopy (AFM) techniques can be used to manipulate single molecules, both in real time and under physiological conditions, and are ideally suited to directly quantify the forces involved in both intra- and intermolecular protein interactions. In combination with molecular biology and computer simulations, these techniques have been applied to characterize the unfolding and refolding reactions in a variety of proteins, such as titin (an elastic mechano-sensing protein found in muscle) and polycystin-1 (PC1, a mechanosensor found in the kidney).

scholarly journals Local frustration around enzyme active sites

2019 ◽  
Vol 116 (10) ◽  
pp. 4037-4043 ◽  
Author(s):  
Maria I. Freiberger ◽  
A. Brenda Guzovsky ◽  
Peter G. Wolynes ◽  
R. Gonzalo Parra ◽  
Diego U. Ferreiro
Keyword(s):  
Primary Structure ◽  
Active Sites ◽  
Protein Sequences ◽  
Structure And Function ◽  
Energy Landscapes ◽  
Biological Functions ◽  
Complex Energy ◽  
Oligomeric State ◽  
Catalytic Sites ◽  
And Function

Conflicting biological goals often meet in the specification of protein sequences for structure and function. Overall, strong energetic conflicts are minimized in folded native states according to the principle of minimal frustration, so that a sequence can spontaneously fold, but local violations of this principle open up the possibility to encode the complex energy landscapes that are required for active biological functions. We survey the local energetic frustration patterns of all protein enzymes with known structures and experimentally annotated catalytic residues. In agreement with previous hypotheses, the catalytic sites themselves are often highly frustrated regardless of the protein oligomeric state, overall topology, and enzymatic class. At the same time a secondary shell of more weakly frustrated interactions surrounds the catalytic site itself. We evaluate the conservation of these energetic signatures in various family members of major enzyme classes, showing that local frustration is evolutionarily more conserved than the primary structure itself.

scholarly journals Structure of nonstructural protein 1 from SARS-CoV-2.

2020 ◽  
Author(s):  
Lauren K. Clark ◽  
Todd J. Green ◽  
Chad M. Petit
Keyword(s):  
Crystal Structure ◽  
Life Cycle ◽  
High Resolution ◽  
Nonstructural Protein ◽  
Critical Role ◽  
Viral Life Cycle ◽  
Structure And Function ◽  
Future Studies ◽  
Nonstructural Protein 1 ◽  
And Function

The periodic emergence of novel coronaviruses (CoVs) represents an ongoing public health concern with significant health and financial burden worldwide. The most recent occurrence originated in the city of Wuhan, China where a novel coronavirus (SARS-CoV-2) emerged causing severe respiratory illness and pneumonia. The continual emergence of novel coronaviruses underscores the importance of developing effective vaccines as well as novel therapeutic options that target either viral functions or host factors recruited to support coronavirus replication. The CoV nonstructural protein 1 (nsp1) has been shown to promote cellular mRNA degradation, block host cell translation, and inhibit the innate immune response to virus infection. Interestingly, deletion of the nsp1-coding region in infectious clones prevented the virus from productively infecting cultured cells. Because of nsp1’s importance in the CoV life cycle, it has been highlighted as a viable target for both antiviral therapy and vaccine development. However, the fundamental molecular and structural mechanisms that underlie nsp1 function remain poorly understood, despite its critical role in the viral life cycle. Here we report the high-resolution crystal structure of the amino, globular portion of SARS-CoV-2 nsp1 (residues 10 – 127) at 1.77 Å resolution. A comparison of our structure with the SARS-CoV-1 nsp1 structure reveals how mutations alter the conformation of flexible loops, inducing the formation of novel secondary structural elements and new surface features. Paired with the recently published structure of the carboxyl end of nsp1 (residues 148 – 180), our results provide the groundwork for future studies focusing on SARS-CoV-2 nsp1 structure and function during the viral life cycle. IMPORTANCE The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent for the COVID-19 pandemic. One protein known to play a critical role in the coronavirus life cycle is nonstructural protein1 (nsp1). As such, it has been highlighted in numerous studies as a target for both the development of antivirals and for the design of live-attenuated vaccines. Here we report the high-resolution crystal structure of nsp1 derived from SARS-CoV-2 at 1.77 Å resolution. This structure will facilitate future studies focusing on understanding the relationship between structure and function for nsp1. In turn, understanding these structure-function relationships will allow nsp1 to be fully exploited as a target for both antiviral development and vaccine design.

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