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Yorodumi- PDB-6vw2: Cryo-EM structure of human islet amyloid polypeptide (hIAPP, or a... -
+Open data
-Basic information
Entry | Database: PDB / ID: 6vw2 | ||||||
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Title | Cryo-EM structure of human islet amyloid polypeptide (hIAPP, or amylin) fibrils | ||||||
Components | Islet amyloid polypeptide (SUMO-tagged) | ||||||
Keywords | PROTEIN FIBRIL / hIAPP / type II diabetes / amyloid | ||||||
Function / homology | Function and homology information SUMO is conjugated to E1 (UBA2:SAE1) / SUMOylation of nuclear envelope proteins / SUMO is transferred from E1 to E2 (UBE2I, UBC9) / SUMOylation of SUMOylation proteins / SUMO is proteolytically processed / : / SUMOylation of transcription factors / Postmitotic nuclear pore complex (NPC) reformation / SUMOylation of transcription cofactors / septin ring ...SUMO is conjugated to E1 (UBA2:SAE1) / SUMOylation of nuclear envelope proteins / SUMO is transferred from E1 to E2 (UBE2I, UBC9) / SUMOylation of SUMOylation proteins / SUMO is proteolytically processed / : / SUMOylation of transcription factors / Postmitotic nuclear pore complex (NPC) reformation / SUMOylation of transcription cofactors / septin ring / SUMOylation of DNA damage response and repair proteins / SUMOylation of RNA binding proteins / amylin receptor signaling pathway / Calcitonin-like ligand receptors / SUMOylation of DNA replication proteins / SUMOylation of chromatin organization proteins / negative regulation of amyloid fibril formation / negative regulation of bone resorption / eating behavior / ubiquitin-like protein ligase binding / negative regulation of osteoclast differentiation / positive regulation of protein kinase A signaling / Regulation of gene expression in beta cells / protein sumoylation / negative regulation of protein-containing complex assembly / positive regulation of cAMP-mediated signaling / positive regulation of calcium-mediated signaling / bone resorption / sensory perception of pain / osteoclast differentiation / condensed nuclear chromosome / hormone activity / protein tag activity / cell-cell signaling / amyloid-beta binding / G alpha (s) signalling events / positive regulation of MAPK cascade / receptor ligand activity / positive regulation of apoptotic process / Amyloid fiber formation / signaling receptor binding / lipid binding / apoptotic process / signal transduction / extracellular space / extracellular region / identical protein binding / nucleus Similarity search - Function | ||||||
Biological species | Saccharomyces cerevisiae (brewer's yeast) Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.4 Å | ||||||
Authors | Cao, Q. / Boyer, D.R. / Sawaya, M.R. / Eisenberg, D.S. | ||||||
Funding support | United States, 1items
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Citation | Journal: Nat Struct Mol Biol / Year: 2020 Title: Cryo-EM structure and inhibitor design of human IAPP (amylin) fibrils. Authors: Qin Cao / David R Boyer / Michael R Sawaya / Peng Ge / David S Eisenberg / Abstract: Human islet amyloid polypeptide (hIAPP) functions as a glucose-regulating hormone but deposits as amyloid fibrils in more than 90% of patients with type II diabetes (T2D). Here we report the cryo-EM ...Human islet amyloid polypeptide (hIAPP) functions as a glucose-regulating hormone but deposits as amyloid fibrils in more than 90% of patients with type II diabetes (T2D). 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. Our hIAPP fibril structure (i) supports the previous hypothesis that residues 20-29 constitute the core of the hIAPP amyloid; (ii) suggests a molecular mechanism for the action of the hIAPP hereditary mutation S20G; (iii) explains why the six residue substitutions in rodent IAPP prevent aggregation; and (iv) suggests regions responsible for the observed hIAPP cross-seeding with β-amyloid. Furthermore, we performed structure-based inhibitor design to generate potential hIAPP aggregation inhibitors. Four of the designed peptides 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. | ||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 6vw2.cif.gz | 67.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6vw2.ent.gz | 41.1 KB | Display | PDB format |
PDBx/mmJSON format | 6vw2.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/vw/6vw2 ftp://data.pdbj.org/pub/pdb/validation_reports/vw/6vw2 | HTTPS FTP |
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-Related structure data
Related structure data | 21410MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | |
EM raw data | EMPIAR-10871 (Title: Cryo electron microscopy of recombinant, un-seeded hIAPP fibrils Data size: 1.9 TB Data #1: Unaligned K2 movies of unseeded, recombinant hIAPP amyloid fibrils [micrographs - multiframe]) |
-Links
-Assembly
Deposited unit |
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-Components
#1: Protein | Mass: 17274.273 Da / Num. of mol.: 10 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (yeast), (gene. exp.) Homo sapiens (human) Strain: ATCC 204508 / S288c / Gene: SMT3, YDR510W, D9719.15, IAPP / Production host: Escherichia coli (E. coli) / References: UniProt: Q12306, UniProt: P10997 |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: FILAMENT / 3D reconstruction method: helical reconstruction |
-Sample preparation
Component | Name: hIAPP fibril / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Escherichia coli (E. coli) |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 2000 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm |
Image recording | Average exposure time: 8 sec. / Electron dose: 44 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||
Helical symmerty | Angular rotation/subunit: 179.42 ° / Axial rise/subunit: 2.406 Å / Axial symmetry: C1 | ||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 25767 / Symmetry type: HELICAL |