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- PDB-7p6s: Crystal structure of the FimH-binding decoy module of human glyco... -

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Entry
Database: PDB / ID: 7p6s
TitleCrystal structure of the FimH-binding decoy module of human glycoprotein 2 (GP2) (crystal form II)
ComponentsIsoform Alpha of Pancreatic secretory granule membrane major glycoprotein GP2
KeywordsANTIMICROBIAL PROTEIN / Extracellular matrix / glycoprotein / N-glycan / structural protein / decoy module / D10C domain / D8C sequence / pancreas / intestine / mucosal immunity / FimH / AlphaFold
Function / homology
Function and homology information


antigen transcytosis by M cells in mucosal-associated lymphoid tissue / zymogen granule membrane / Post-translational modification: synthesis of GPI-anchored proteins / neutrophil migration / antigen binding / endosome / membrane raft / apical plasma membrane / external side of plasma membrane / innate immune response ...antigen transcytosis by M cells in mucosal-associated lymphoid tissue / zymogen granule membrane / Post-translational modification: synthesis of GPI-anchored proteins / neutrophil migration / antigen binding / endosome / membrane raft / apical plasma membrane / external side of plasma membrane / innate immune response / cell surface / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
: / Zona pellucida domain, conserved site / Zona pellucida, ZP-C domain / ZP domain signature. / Zona pellucida-like domain / Zona pellucida (ZP) domain / ZP domain profile. / Zona pellucida domain
Similarity search - Domain/homology
pentane-1,5-diol / Pancreatic secretory granule membrane major glycoprotein GP2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.35 Å
AuthorsStsiapanava, A. / Tunyasuvunakool, K. / Jumper, J. / de Sanctis, D. / Jovine, L.
Funding support Sweden, 3items
OrganizationGrant numberCountry
Swedish Research Council2016-03999 Sweden
Swedish Research Council2020-04936 Sweden
Knut and Alice Wallenberg Foundation2018.0042 Sweden
Citation
Journal: Nat Struct Mol Biol / Year: 2022
Title: Structure of the decoy module of human glycoprotein 2 and uromodulin and its interaction with bacterial adhesin FimH.
Authors: Alena Stsiapanava / Chenrui Xu / Shunsuke Nishio / Ling Han / Nao Yamakawa / Marta Carroni / Kathryn Tunyasuvunakool / John Jumper / Daniele de Sanctis / Bin Wu / Luca Jovine /
Abstract: Glycoprotein 2 (GP2) and uromodulin (UMOD) filaments protect against gastrointestinal and urinary tract infections by acting as decoys for bacterial fimbrial lectin FimH. By combining AlphaFold2 ...Glycoprotein 2 (GP2) and uromodulin (UMOD) filaments protect against gastrointestinal and urinary tract infections by acting as decoys for bacterial fimbrial lectin FimH. By combining AlphaFold2 predictions with X-ray crystallography and cryo-EM, we show that these proteins contain a bipartite decoy module whose new fold presents the high-mannose glycan recognized by FimH. The structure rationalizes UMOD mutations associated with kidney diseases and visualizes a key epitope implicated in cast nephropathy.
#1: Journal: Biochim.Biophys.Acta / Year: 1978
Title: Glycoprotein synthesis in the adult rat pancreas. IV. Subcellular distribution of membrane glycoproteins.
Authors: Ronzio, R.A. / Kronquist, K.E. / Lewis, D.S. / MacDonald, R.J. / Mohrlok, S.H. / O'Donnell Jr., J.J.
#2: Journal: Biochim.Biophys.Acta / Year: 2000
Title: Molecular cloning and sequences of cDNAs encoding alpha (large) and beta (small) isoforms of human pancreatic zymogen granule membrane-associated protein GP2.
Authors: Fukuoka, S.
#3: Journal: Biochem.Biophys.Res.Commun. / Year: 2004
Title: GP2/THP gene family of self-binding, GPI-anchored proteins forms a cluster at chromosome 7F1 region in mouse genome.
Authors: Kobayashi, K. / Yanagihara, K. / Ishiguro, K. / Fukuoka, S.
#4: Journal: FEBS Lett / Year: 2004
Title: Identification and characterization of D8C, a novel domain present in liver-specific LZP, uromodulin and glycoprotein 2, mutated in familial juvenile hyperuricaemic nephropathy.
Authors: Huirong Yang / Chaoqun Wu / Shouyuan Zhao / Jinhu Guo /
Abstract: Present work reported a novel domain--D8C (domain with conserved eight cysteines in liver-specific ZP domain-containing protein, glycoprotein 2 (GP-2) and uromodulin (UMOD)), present in liver- ...Present work reported a novel domain--D8C (domain with conserved eight cysteines in liver-specific ZP domain-containing protein, glycoprotein 2 (GP-2) and uromodulin (UMOD)), present in liver-specific LZP, UMOD, GP-2 and some uncharacterized proteins, most of which are membrane proteins, extracellular proteins or nuclear membrane proteins. D8C contains eight well-conserved cysteine residues, which were predicted to form four pairs of disulfide bridges. D8C is composed mainly of beta-strands. Mutation in the D8C at Cys217 in human UMOD is associated with familial juvenile hyperuricaemic nephropathy, which might be due to the disruption of the disulfide bridge. Identification of D8C would further the understandings of related proteins.
#5: Journal: BMC Gastroenterol / Year: 2009
Title: The pancreatic zymogen granule membrane protein, GP2, binds Escherichia coli Type 1 fimbriae.
Authors: Yu, S. / Lowe, A.W.
#6: Journal: Nature / Year: 2009
Title: Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response.
Authors: Hase, K. / Kawano, K. / Nochi, T. / Pontes, G.S. / Fukuda, S. / Ebisawa, M. / Kadokura, K. / Tobe, T. / Fujimura, Y. / Kawano, S. / Yabashi, A. / Waguri, S. / Nakato, G. / Kimura, S. / ...Authors: Hase, K. / Kawano, K. / Nochi, T. / Pontes, G.S. / Fukuda, S. / Ebisawa, M. / Kadokura, K. / Tobe, T. / Fujimura, Y. / Kawano, S. / Yabashi, A. / Waguri, S. / Nakato, G. / Kimura, S. / Murakami, T. / Iimura, M. / Hamura, K. / Fukuoka, S. / Lowe, A.W. / Itoh, K. / Kiyono, H. / Ohno, H.
#7: Journal: Gut / Year: 2009
Title: Identification of GP2, the major zymogen granule membrane glycoprotein, as the autoantigen of pancreatic antibodies in Crohn's disease.
Authors: Roggenbuck, D. / Hausdorf, G. / Martinez-Gamboa, L. / Reinhold, D. / Buttner, T. / Jungblut, P.R. / Porstmann, T. / Laass, M.W. / Henker, J. / Buning, C. / Feist, E. / Conrad, K.
#8: Journal: Clin.Chim.Acta / Year: 2012
Title: Autoantibodies to GP2, the major zymogen granule membrane glycoprotein, in patients with gluten-sensitive enteropathy: a possible serological trap.
Authors: Bonaci-Nikolic, B. / Spuran, M. / Andrejevic, S. / Nikolic, M.
#9: Journal: Nature / Year: 2021
Title: Highly accurate protein structure prediction with AlphaFold.
Authors: John Jumper / Richard Evans / Alexander Pritzel / Tim Green / Michael Figurnov / Olaf Ronneberger / Kathryn Tunyasuvunakool / Russ Bates / Augustin Žídek / Anna Potapenko / Alex Bridgland ...Authors: John Jumper / Richard Evans / Alexander Pritzel / Tim Green / Michael Figurnov / Olaf Ronneberger / Kathryn Tunyasuvunakool / Russ Bates / Augustin Žídek / Anna Potapenko / Alex Bridgland / Clemens Meyer / Simon A A Kohl / Andrew J Ballard / Andrew Cowie / Bernardino Romera-Paredes / Stanislav Nikolov / Rishub Jain / Jonas Adler / Trevor Back / Stig Petersen / David Reiman / Ellen Clancy / Michal Zielinski / Martin Steinegger / Michalina Pacholska / Tamas Berghammer / Sebastian Bodenstein / David Silver / Oriol Vinyals / Andrew W Senior / Koray Kavukcuoglu / Pushmeet Kohli / Demis Hassabis /
Abstract: Proteins are essential to life, and understanding their structure can facilitate a mechanistic understanding of their function. Through an enormous experimental effort, the structures of around ...Proteins are essential to life, and understanding their structure can facilitate a mechanistic understanding of their function. Through an enormous experimental effort, the structures of around 100,000 unique proteins have been determined, but this represents a small fraction of the billions of known protein sequences. Structural coverage is bottlenecked by the months to years of painstaking effort required to determine a single protein structure. Accurate computational approaches are needed to address this gap and to enable large-scale structural bioinformatics. Predicting the three-dimensional structure that a protein will adopt based solely on its amino acid sequence-the structure prediction component of the 'protein folding problem'-has been an important open research problem for more than 50 years. Despite recent progress, existing methods fall far short of atomic accuracy, especially when no homologous structure is available. Here we provide the first computational method that can regularly predict protein structures with atomic accuracy even in cases in which no similar structure is known. We validated an entirely redesigned version of our neural network-based model, AlphaFold, in the challenging 14th Critical Assessment of protein Structure Prediction (CASP14), demonstrating accuracy competitive with experimental structures in a majority of cases and greatly outperforming other methods. Underpinning the latest version of AlphaFold is a novel machine learning approach that incorporates physical and biological knowledge about protein structure, leveraging multi-sequence alignments, into the design of the deep learning algorithm.
History
DepositionJul 17, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 16, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.pdbx_database_id_PubMed ..._citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Mar 30, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3May 1, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Isoform Alpha of Pancreatic secretory granule membrane major glycoprotein GP2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,4574
Polymers17,9111
Non-polymers5473
Water4,179232
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area420 Å2
ΔGint4 kcal/mol
Surface area7380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)33.480, 59.500, 87.040
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Isoform Alpha of Pancreatic secretory granule membrane major glycoprotein GP2 / Pancreatic zymogen granule membrane protein GP-2 / ZAP75


Mass: 17910.852 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GP2 / Plasmid: pLJ6 / Cell line (production host): Expi293F GnTI- / Production host: Homo sapiens (human) / References: UniProt: P55259
#2: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#3: Chemical ChemComp-9JE / pentane-1,5-diol / Pentane-1,5-diol


Mass: 104.148 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H12O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 232 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.42 Å3/Da / Density % sol: 49.27 % / Description: Plate
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 20% (v/v) 1,5-pentanediol, 10% (w/v) PEG 8K, 0.1 M GlyGly/AMPD pH 8.5, 0.5 mM YCl3, 0.5 mM ErCl3, 0.5 mM TbCl3, 0.5 mM YbCl3, 20 mM Na-HEPES pH 7.5, 150 mM NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.976254 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 18, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976254 Å / Relative weight: 1
ReflectionResolution: 1.35→49.12 Å / Num. obs: 38991 / % possible obs: 99.7 % / Redundancy: 6 % / Biso Wilson estimate: 13.25 Å2 / CC1/2: 1 / CC star: 1 / Rmerge(I) obs: 0.153 / Rpim(I) all: 0.067 / Rrim(I) all: 0.167 / Net I/σ(I): 7
Reflection shellResolution: 1.35→1.39 Å / Redundancy: 4.7 % / Rmerge(I) obs: 2.318 / Mean I/σ(I) obs: 0.7 / Num. unique obs: 2960 / CC1/2: 0.4 / CC star: 0.75 / Rpim(I) all: 1.18 / Rrim(I) all: 2.612 / % possible all: 98.2

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Processing

Software
NameVersionClassification
MxCuBE3data collection
XDSFeb 5, 2021 BUILT=20210322data reduction
XSCALEFeb 5, 2021 BUILT=20210322data scaling
PHASER2.8.3phasing
Coot0.9.5model building
ISOLDE1.1refinement
PHENIXdev-4282refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Partially refined model of crystal form I of the same protein (PDB D_1292117104)

Resolution: 1.35→49.12 Å / SU ML: 0.1991 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.0674
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2244 2027 5.21 %
Rwork0.1942 36914 -
obs0.1957 38941 99.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 18.48 Å2
Refinement stepCycle: LAST / Resolution: 1.35→49.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1096 0 35 232 1363
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00411195
X-RAY DIFFRACTIONf_angle_d0.72221631
X-RAY DIFFRACTIONf_chiral_restr0.0691168
X-RAY DIFFRACTIONf_plane_restr0.0085216
X-RAY DIFFRACTIONf_dihedral_angle_d13.9095422
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.35-1.380.42161410.4262556X-RAY DIFFRACTION98.04
1.38-1.420.36771420.37382591X-RAY DIFFRACTION99.67
1.42-1.460.36211430.33782598X-RAY DIFFRACTION99.93
1.46-1.510.35581420.30692600X-RAY DIFFRACTION99.78
1.51-1.560.28481430.27222604X-RAY DIFFRACTION99.85
1.56-1.630.28841440.25062612X-RAY DIFFRACTION99.89
1.63-1.70.22491440.22752622X-RAY DIFFRACTION99.89
1.7-1.790.2281430.20542612X-RAY DIFFRACTION99.89
1.79-1.90.24711450.20172638X-RAY DIFFRACTION99.93
1.9-2.050.21851450.18412644X-RAY DIFFRACTION99.93
2.05-2.260.21881450.17242642X-RAY DIFFRACTION99.93
2.26-2.580.17481460.15982668X-RAY DIFFRACTION99.58
2.58-3.250.17371480.15642692X-RAY DIFFRACTION99.82
3.25-49.120.19331560.1552835X-RAY DIFFRACTION99.77

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