+Open data
-Basic information
Entry | Database: PDB / ID: 7y5n | ||||||
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Title | Structure of 1:1 PAPP-A.ProMBP complex(half map) | ||||||
Components |
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Keywords | METAL BINDING PROTEIN/HYDROLASE / Hydrolase / METAL BINDING PROTEIN-HYDROLASE complex | ||||||
Function / homology | Function and homology information extracellular matrix structural constituent conferring compression resistance / defense response to nematode / pappalysin-1 / response to follicle-stimulating hormone / negative regulation of macrophage cytokine production / protein metabolic process / negative regulation of interleukin-10 production / response to dexamethasone / positive regulation of interleukin-4 production / transport vesicle ...extracellular matrix structural constituent conferring compression resistance / defense response to nematode / pappalysin-1 / response to follicle-stimulating hormone / negative regulation of macrophage cytokine production / protein metabolic process / negative regulation of interleukin-10 production / response to dexamethasone / positive regulation of interleukin-4 production / transport vesicle / female pregnancy / protein catabolic process / metalloendopeptidase activity / metallopeptidase activity / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / heparin binding / carbohydrate binding / collagen-containing extracellular matrix / ficolin-1-rich granule lumen / cell surface receptor signaling pathway / defense response to bacterium / immune response / Neutrophil degranulation / proteolysis / extracellular space / extracellular exosome / zinc ion binding / extracellular region Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.45 Å | ||||||
Authors | Zhong, Q.H. / Chu, H.L. / Wang, G.P. / Zhang, C. / Wei, Y. / Qiao, J. / Hang, J. | ||||||
Funding support | China, 1items
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Citation | Journal: Cell Discov / Year: 2022 Title: Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2. Authors: Qihang Zhong / Honglei Chu / Guopeng Wang / Cheng Zhang / Rong Li / Fusheng Guo / Xinlu Meng / Xiaoguang Lei / Youli Zhou / Ruobing Ren / Lin Tao / Ningning Li / Ning Gao / Yuan Wei / Jie Qiao / Jing Hang / Abstract: Originally discovered in the circulation of pregnant women as a protein secreted by placental trophoblasts, the metalloprotease pregnancy-associated plasma protein A (PAPP-A) is also widely expressed ...Originally discovered in the circulation of pregnant women as a protein secreted by placental trophoblasts, the metalloprotease pregnancy-associated plasma protein A (PAPP-A) is also widely expressed by many other tissues. It cleaves insulin-like growth factor-binding proteins (IGFBPs) to increase the bioavailability of IGFs and plays essential roles in multiple growth-promoting processes. While the vast majority of the circulatory PAPP-A in pregnancy is proteolytically inactive due to covalent inhibition by proform of eosinophil major basic protein (proMBP), the activity of PAPP-A can also be covalently inhibited by another less characterized modulator, stanniocalcin-2 (STC2). However, the structural basis of PAPP-A proteolysis and the mechanistic differences between these two modulators are poorly understood. Here we present two cryo-EM structures of endogenous purified PAPP-A in complex with either proMBP or STC2. Both modulators form 2:2 heterotetramer with PAPP-A and establish extensive interactions with multiple domains of PAPP-A that are distal to the catalytic cleft. This exosite-binding property results in a steric hindrance to prevent the binding and cleavage of IGFBPs, while the IGFBP linker region-derived peptides harboring the cleavage sites are no longer sensitive to the modulator treatment. Functional investigation into proMBP-mediated PAPP-A regulation in selective intrauterine growth restriction (sIUGR) pregnancy elucidates that PAPP-A and proMBP collaboratively regulate extravillous trophoblast invasion and the consequent fetal growth. Collectively, our work reveals a novel covalent exosite-competitive inhibition mechanism of PAPP-A and its regulatory effect on placental function. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7y5n.cif.gz | 324.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7y5n.ent.gz | 246.3 KB | Display | PDB format |
PDBx/mmJSON format | 7y5n.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/y5/7y5n ftp://data.pdbj.org/pub/pdb/validation_reports/y5/7y5n | HTTPS FTP |
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-Related structure data
Related structure data | 33621MC 7y5qC 8hggC 8hghC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 2 types, 3 molecules ACD
#1: Protein | Mass: 25236.564 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P13727 |
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#2: Protein | Mass: 172475.484 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: Q13219, pappalysin-1 |
-Sugars , 2 types, 11 molecules
#3: Polysaccharide | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source |
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#4: Sugar | ChemComp-NAG / |
-Non-polymers , 2 types, 8 molecules
#5: Chemical | ChemComp-ZN / |
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#6: Chemical | ChemComp-CA / |
-Details
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 |
-Sample preparation
Component | Name: Structure of 1:1 PAPP-A/ProMBP complex(half map) / Type: COMPLEX / Entity ID: #1-#2 / Source: NATURAL |
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Source (natural) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
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: 1200 nm / Nominal defocus min: 700 nm |
Specimen holder | Cryogen: NITROGEN |
Image recording | Electron dose: 60.1 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k) |
EM imaging optics | Energyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV |
-Processing
Software | Name: PHENIX / Version: 1.19.1_4122: / Classification: refinement | ||||||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.45 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 142469 / Symmetry type: POINT | ||||||||||||||||||||||||||||
Refine LS restraints |
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