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Open data
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Basic information
Entry | Database: PDB / ID: 8a7d | ||||||
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Title | Partial dimer complex of PAPP-A and its inhibitor STC2 | ||||||
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![]() | HYDROLASE / Metzincin metalloprotease Inhibitor complex | ||||||
Function / homology | ![]() regulation of hormone biosynthetic process / pappalysin-1 / response to follicle-stimulating hormone / regulation of store-operated calcium entry / protein metabolic process / response to vitamin D / negative regulation of multicellular organism growth / response to dexamethasone / decidualization / endoplasmic reticulum unfolded protein response ...regulation of hormone biosynthetic process / pappalysin-1 / response to follicle-stimulating hormone / regulation of store-operated calcium entry / protein metabolic process / response to vitamin D / negative regulation of multicellular organism growth / response to dexamethasone / decidualization / endoplasmic reticulum unfolded protein response / embryo implantation / female pregnancy / Post-translational protein phosphorylation / protein catabolic process / hormone activity / response to peptide hormone / metalloendopeptidase activity / intracellular calcium ion homeostasis / metallopeptidase activity / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cellular response to hypoxia / response to oxidative stress / cell surface receptor signaling pathway / endoplasmic reticulum lumen / negative regulation of gene expression / heme binding / perinuclear region of cytoplasm / Golgi apparatus / enzyme binding / endoplasmic reticulum / protein homodimerization activity / proteolysis / extracellular space / zinc ion binding / extracellular region Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.06 Å | ||||||
![]() | Kobbero, S.D. / Gajhede, M. / Mirza, O.A. / Boesen, T. / Oxvig, C. | ||||||
Funding support | ![]()
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![]() | ![]() Title: Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism. Authors: Sara Dam Kobberø / Michael Gajhede / Osman Asghar Mirza / Søren Kløverpris / Troels Rønn Kjær / Jakob Hauge Mikkelsen / Thomas Boesen / Claus Oxvig / ![]() Abstract: The metzincin metalloproteinase PAPP-A plays a key role in the regulation of insulin-like growth factor (IGF) signaling by specific cleavage of inhibitory IGF binding proteins (IGFBPs). Using single- ...The metzincin metalloproteinase PAPP-A plays a key role in the regulation of insulin-like growth factor (IGF) signaling by specific cleavage of inhibitory IGF binding proteins (IGFBPs). Using single-particle cryo-electron microscopy (cryo-EM), we here report the structure of PAPP-A in complex with its endogenous inhibitor, stanniocalcin-2 (STC2), neither of which have been reported before. The highest resolution (3.1 Å) was obtained for the STC2 subunit and the N-terminal approximately 1000 residues of the PAPP-A subunit. The 500 kDa 2:2 PAPP-A·STC2 complex is a flexible multidomain ensemble with numerous interdomain contacts. In particular, a specific disulfide bond between the subunits of STC2 and PAPP-A prevents dissociation, and interactions between STC2 and a module located in the very C-terminal end of the PAPP-A subunit prevent binding of its main substrate, IGFBP-4. While devoid of activity towards IGFBP-4, the active site cleft of the catalytic domain is accessible in the inhibited PAPP-A·STC2 complex, as shown by its ability to hydrolyze a synthetic peptide derived from IGFBP-4. Relevant to multiple human pathologies, this unusual mechanism of proteolytic inhibition may support the development of specific pharmaceutical agents, by which IGF signaling can be indirectly modulated. | ||||||
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 314.8 KB | Display | ![]() |
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PDB format | ![]() | 231.4 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.4 MB | Display | ![]() |
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Full document | ![]() | 1.5 MB | Display | |
Data in XML | ![]() | 49.6 KB | Display | |
Data in CIF | ![]() | 74.9 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 15220MC ![]() 8a7eC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 171143.047 Da / Num. of mol.: 2 / Mutation: E563Q Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() #2: Protein | | Mass: 18819.811 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() #3: Sugar | ChemComp-NAG / #4: Chemical | ChemComp-ZN / | #5: Chemical | ChemComp-CA / Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
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Buffer solution | pH: 7.4 Details: Hepes buffer, 20 mM Hepes pH 7.4 100 mM NaCl, 1 mM CaCl | ||||||||||||||||||||||||||||||||||||||||||
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Specimen | Conc.: 0.6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||||||||||||||||||||
Specimen support | Grid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: C-flat-2/2 | ||||||||||||||||||||||||||||||||||||||||||
Vitrification | Instrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 277.15 K / Details: 4 s |
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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: ![]() | |||||||||||||||||||||
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 600 nm | |||||||||||||||||||||
Image recording |
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Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||
Particle selection | Num. of particles selected: 6677370 / Details: Combined two datasets | |||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | |||||||||||||||||||||||||
3D reconstruction | Resolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 278982 / Num. of class averages: 1 / Symmetry type: POINT | |||||||||||||||||||||||||
Atomic model building |
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