Cryo-EM structure and inhibitor design of human IAPP (amylin) fibrils
| Autor: | Michael R. Sawaya, Qin Cao, Peng Ge, David Eisenberg, David R. Boyer |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Cryo-electron microscopy Protein Conformation Drug Evaluation Preclinical Amylin Neurodegenerative Medical and Health Sciences law.invention 0302 clinical medicine Protein structure Models Structural Biology law 2.1 Biological and endogenous factors Aetiology chemistry.chemical_classification 0303 health sciences geography.geographical_feature_category Diabetes Biological Sciences Islet Preclinical Recombinant Proteins Amino acid Islet Amyloid Polypeptide 5.1 Pharmaceuticals Molecular mechanism Recombinant DNA Development of treatments and therapeutic interventions Type 2 Amyloid 1.1 Normal biological development and functioning Biophysics Rodentia macromolecular substances Fibril Article 03 medical and health sciences Underpinning research Diabetes Mellitus Animals Humans Molecular Biology Metabolic and endocrine 030304 developmental biology geography Cryoelectron Microscopy Molecular In vitro chemistry Diabetes Mellitus Type 2 Drug Design Chemical Sciences Mutation Drug Evaluation Peptides 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Nature structural & molecular biology Nature structural & molecular biology, vol 27, iss 7 |
| ISSN: | 1545-9985 1545-9993 |
| Popis: | Human islet amyloid polypeptide (hIAPP, or amylin) is a 37 amino acid hormone secreted by pancreatic islet β-cells. Aggregation of hIAPP into amyloid fibrils is found in more than 90% of Type-II Diabetes (T2D) patients and is considered to be associated with T2D pathology. Although different models have been proposed, the high resolution structure of hIAPP fibrils is unknown. Here we report the cryo-EM structure of recombinant full-length hIAPP fibrils. The fibril is composed of two symmetrically-related protofilaments with ordered residues 14-37 that meet at a 14-residue central hydrophobic core. Our hIAPP fibril structure (i) supports the previous hypothesis that residues 20-29, especially 23-29 are the primary amyloid core of hIAPP, (ii) suggests a molecular mechanism for the action of the hIAPP hereditary mutation S20G, (iii) explains why the 6 residue substitutions in rodent IAPP prevent aggregation, and (iv) suggests possible regions responsible for the observed hIAPP cross-seeding with β-amyloid. Furthermore, we performed structure-based inhibitor design to generate potential hIAPP aggregation inhibitors via a capping strategy. Four of the designed candidates delay hIAPP aggregation in vitro, providing a starting point for the development of T2D therapeutics and proof-of-concept that the capping strategy can be used on full-length cryo-EM fibril structures. |
| Databáze: | OpenAIRE |
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