Abstract
Protein aggregation correlates with the development of several deleterious human disorders such as Alzheimers disease, Parkinsons disease, prion-associated transmissible spongiform encephalopathies and type II diabetes. The polypeptides involved in these disorders may be globular proteins with a defined 3D-structure or natively unfolded proteins in their soluble conformations. In either case, proteins associated with these pathogeneses all aggregate into amyloid fibrils sharing a common structure, in which β-strands of polypeptide chains are perpendicular to the fibril axis. Because of the prominence of amyloid deposits in many of these diseases, much effort has gone into elucidating the structural basis of protein aggregation. A number of recent experimental and theoretical studies have significantly increased our understanding of the process. On the one hand, solid-state NMR, X-ray crystallography and single molecule methods have provided us with the first high-resolution 3D structures of amyloids, showing that they exhibit conformational plasticity and are able to adopt different stable tertiary folds. On the other hand, several computational approaches have identified regions prone to aggregation in disease-linked polypeptides, predicted the differential aggregation propensities of their genetic variants and simulated the early, crucial steps in protein self-assembly. This review summarizes these findings and their therapeutic relevance, as by uncovering specific structural or sequential targets they may provide us with a means to tackle the debilitating diseases linked to protein aggregation.
Keywords: Conformational diseases, amyloid fibrils, protein aggregation, protein folding, protein structure, Alzheimer's disease, Parkinson's disease, prion
Current Medicinal Chemistry
Title: Recent Structural and Computational Insights into Conformational Diseases
Volume: 15 Issue: 13
Author(s): Xavier Fernandez-Busquets, Natalia S. de Groot, Daniel Fernandez and Salvador Ventura
Affiliation:
Keywords: Conformational diseases, amyloid fibrils, protein aggregation, protein folding, protein structure, Alzheimer's disease, Parkinson's disease, prion
Abstract: Protein aggregation correlates with the development of several deleterious human disorders such as Alzheimers disease, Parkinsons disease, prion-associated transmissible spongiform encephalopathies and type II diabetes. The polypeptides involved in these disorders may be globular proteins with a defined 3D-structure or natively unfolded proteins in their soluble conformations. In either case, proteins associated with these pathogeneses all aggregate into amyloid fibrils sharing a common structure, in which β-strands of polypeptide chains are perpendicular to the fibril axis. Because of the prominence of amyloid deposits in many of these diseases, much effort has gone into elucidating the structural basis of protein aggregation. A number of recent experimental and theoretical studies have significantly increased our understanding of the process. On the one hand, solid-state NMR, X-ray crystallography and single molecule methods have provided us with the first high-resolution 3D structures of amyloids, showing that they exhibit conformational plasticity and are able to adopt different stable tertiary folds. On the other hand, several computational approaches have identified regions prone to aggregation in disease-linked polypeptides, predicted the differential aggregation propensities of their genetic variants and simulated the early, crucial steps in protein self-assembly. This review summarizes these findings and their therapeutic relevance, as by uncovering specific structural or sequential targets they may provide us with a means to tackle the debilitating diseases linked to protein aggregation.
Export Options
About this article
Cite this article as:
Fernandez-Busquets Xavier, de Groot S. Natalia, Fernandez Daniel and Ventura Salvador, Recent Structural and Computational Insights into Conformational Diseases, Current Medicinal Chemistry 2008; 15 (13) . https://dx.doi.org/10.2174/092986708784534938
DOI https://dx.doi.org/10.2174/092986708784534938 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
The Polyphenol 3, 4, 5 - Tri-hydroxy Benzoic Acid Inhibits Indian Daboia russelli Venom and Its Hemorrhagic Complex Induced Local Toxicity
Current Topics in Medicinal Chemistry Sirolimus and its Analogs and its Effects on Vascular Diseases
Current Pharmaceutical Design Screening, Evaluation, and Early Management of Acute Aortic Dissection in the ED
Current Cardiology Reviews Clinical Applications of Nanotechnology in Atherosclerotic Diseases
Current Nanoscience The Role of Platelets in Athero-Thrombotic Events
Current Pharmaceutical Design Managing Erectile Dysfunction in Heart Failure
Endocrine, Metabolic & Immune Disorders - Drug Targets New Foods, New Consumers: Innovation in Food Product Development
Current Nutrition & Food Science Role of Adiponectin in the Metabolic Syndrome: Current Perspectives on its Modulation as a Treatment Strategy
Current Pharmaceutical Design Mast Cells and Inflammatory Heart Disease: Potential Drug Targets
Cardiovascular & Hematological Disorders-Drug Targets Novel Devices to Prevent Membrane Perforation in Transcrestal Sinus Floor Augmentation Surgery
Recent Patents on Biomedical Engineering (Discontinued) Matrix Metalloproteinase Inhibitors as Prospective Agents for the Prevention and Treatment of Cardiovascular and Neoplastic Diseases
Current Topics in Medicinal Chemistry Cellular Mechanisms of Brain Injury and Cell Death
Current Pharmaceutical Design Non-Peptidic Small-Molecule Antagonists of the Human Platelet Thrombin Receptor PAR-1
Current Medicinal Chemistry - Cardiovascular & Hematological Agents Targeting Inflammation in Primary Cardiovascular Prevention
Current Pharmaceutical Design Pharmacological Management Options to Prevent and Reduce Ischemic Hemorrhagic Transformation
Current Drug Targets Inflammation and Coronary Artery Disease
Current Vascular Pharmacology Integrin Signaling Networks in the Pathobiology of Vascular Smooth Muscle Cells
Vascular Disease Prevention (Discontinued) Recent Advances on the Antiatherogenic Effects of HDL-Derived Proteins and Mimetic Peptides
Current Pharmaceutical Design Targeting Mitochondria in Fighting Cancer
Current Pharmaceutical Design Advances in Irrigated Tip Catheter Technology for Treatment of Cardiac Arrhythmias
Recent Patents on Cardiovascular Drug Discovery