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- PDB-6xja: Streptococcus Pneumoniae IgA1 Protease with IgA1 substrate -

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Basic information

Entry
Database: PDB / ID: 6xja
TitleStreptococcus Pneumoniae IgA1 Protease with IgA1 substrate
Components
  • Immunoglobulin A1 protease
  • Immunoglobulin alpha-1 heavy chain
  • Immunoglobulin alpha-1 light chain
  • Immunoglobulin heavy constant alpha 1
KeywordsIMMUNE SYSTEM / IgA1 / Complex / Protease / metalloprotease
Function / homology
Function and homology information


IgA-specific metalloendopeptidase / secretory dimeric IgA immunoglobulin complex / monomeric IgA immunoglobulin complex / secretory IgA immunoglobulin complex / glomerular filtration / IgA immunoglobulin complex / immunoglobulin complex, circulating / IgG immunoglobulin complex / positive regulation of respiratory burst / Scavenging of heme from plasma ...IgA-specific metalloendopeptidase / secretory dimeric IgA immunoglobulin complex / monomeric IgA immunoglobulin complex / secretory IgA immunoglobulin complex / glomerular filtration / IgA immunoglobulin complex / immunoglobulin complex, circulating / IgG immunoglobulin complex / positive regulation of respiratory burst / Scavenging of heme from plasma / complement activation, classical pathway / antigen binding / Cell surface interactions at the vascular wall / B cell receptor signaling pathway / metalloendopeptidase activity / antibacterial humoral response / blood microparticle / adaptive immune response / immune response / proteolysis / extracellular space / extracellular exosome / zinc ion binding / extracellular region / membrane / plasma membrane
Similarity search - Function
GLUG / The GLUG motif / Peptidase M26, N-terminal domain / Peptidase M26, C-terminal domain / M26 IgA1-specific Metallo-endopeptidase N-terminal region / M26 IgA1-specific Metallo-endopeptidase C-terminal region / G5 domain / G5 domain / G5 domain profile. / G5 ...GLUG / The GLUG motif / Peptidase M26, N-terminal domain / Peptidase M26, C-terminal domain / M26 IgA1-specific Metallo-endopeptidase N-terminal region / M26 IgA1-specific Metallo-endopeptidase C-terminal region / G5 domain / G5 domain / G5 domain profile. / G5 / YSIRK type signal peptide / YSIRK Gram-positive signal peptide / LPXTG cell wall anchor motif / Gram-positive cocci surface proteins LPxTG motif profile. / LPXTG cell wall anchor domain / Immunoglobulin / Immunoglobulin domain / Neutral zinc metallopeptidases, zinc-binding region signature. / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Immunoglobulin heavy constant alpha 1 / Immunoglobulin A1 protease
Similarity search - Component
Biological speciesStreptococcus pneumoniae (bacteria)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsEisenmesser, E.Z. / Zheng, H.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R21 AI146295 United States
CitationJournal: Nat Commun / Year: 2020
Title: Mechanism and inhibition of Streptococcus pneumoniae IgA1 protease.
Authors: Zhiming Wang / Jeremy Rahkola / Jasmina S Redzic / Ying-Chih Chi / Norman Tran / Todd Holyoak / Hongjin Zheng / Edward Janoff / Elan Eisenmesser /
Abstract: Opportunistic pathogens such as Streptococcus pneumoniae secrete a giant metalloprotease virulence factor responsible for cleaving host IgA1, yet the molecular mechanism has remained unknown since ...Opportunistic pathogens such as Streptococcus pneumoniae secrete a giant metalloprotease virulence factor responsible for cleaving host IgA1, yet the molecular mechanism has remained unknown since their discovery nearly 30 years ago despite the potential for developing vaccines that target these enzymes to block infection. Here we show through a series of cryo-electron microscopy single particle reconstructions how the Streptococcus pneumoniae IgA1 protease facilitates IgA1 substrate recognition and how this can be inhibited. Specifically, the Streptococcus pneumoniae IgA1 protease subscribes to an active-site-gated mechanism where a domain undergoes a 10.0 Å movement to facilitate cleavage. Monoclonal antibody binding inhibits this conformational change, providing a direct means to block infection at the host interface. These structural studies explain decades of biological and biochemical studies and provides a general strategy to block Streptococcus pneumoniae IgA1 protease activity to potentially prevent infection.
History
DepositionJun 23, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 20, 2021Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
P: Immunoglobulin A1 protease
A: Immunoglobulin heavy constant alpha 1
B: Immunoglobulin heavy constant alpha 1
L: Immunoglobulin alpha-1 light chain
H: Immunoglobulin alpha-1 heavy chain


Theoretical massNumber of molelcules
Total (without water)235,5805
Polymers235,5805
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area10980 Å2
ΔGint-51 kcal/mol
Surface area91470 Å2

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Components

#1: Protein Immunoglobulin A1 protease / IgA1 protease / IgA-specific zinc metalloproteinase


Mass: 145926.625 Da / Num. of mol.: 1 / Mutation: E1605A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Streptococcus pneumoniae (strain ATCC BAA-255 / R6) (bacteria)
Strain: ATCC BAA-255 / R6 / Gene: iga, spr1042 / Production host: Escherichia coli (E. coli)
References: UniProt: Q59947, IgA-specific metalloendopeptidase
#2: Protein Immunoglobulin heavy constant alpha 1 / Ig alpha-1 chain C region / Ig alpha-1 chain C region BUR / Ig alpha-1 chain C region TRO


Mass: 22887.988 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P01876
#3: Antibody Immunoglobulin alpha-1 light chain


Mass: 21947.256 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
#4: Protein Immunoglobulin alpha-1 heavy chain


Mass: 21930.480 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1IgA1 Protease and IgA1 substrateCOMPLEXall0MULTIPLE SOURCES
2Immunoglobulin A1 proteaseCOMPLEX#11RECOMBINANT
3Immunoglobulin heavy constant alpha 1, Immunoglobulin alpha-1 light chain, Immunoglobulin alpha-1 heavy chainCOMPLEX#2-#41NATURAL
Molecular weightValue: 0.3 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-IDStrain
12Streptococcus pneumoniae (strain ATCC BAA-255 / R6) (bacteria)171101ATCC BAA-255 / R6
23Homo sapiens (human)9606
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7 / Details: 20 mM Hepes, pH 7 150 mM NaCl
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 30 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: dev_3758: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 4 Å / Resolution method: FSC 3 SIGMA CUT-OFF / Num. of particles: 100000 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00816850
ELECTRON MICROSCOPYf_angle_d1.02622881
ELECTRON MICROSCOPYf_dihedral_angle_d17.7772323
ELECTRON MICROSCOPYf_chiral_restr0.0542578
ELECTRON MICROSCOPYf_plane_restr0.0062973

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