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- PDB-6ndj: Crystal structure of human NLRP6 PYD domain with MBP fusion -

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Basic information

Entry
Database: PDB / ID: 6ndj
TitleCrystal structure of human NLRP6 PYD domain with MBP fusion
ComponentsMaltose/maltodextrin-binding periplasmic protein, NACHT, LRR and PYD domains-containing protein 6 chimera
KeywordsSIGNALING PROTEIN / death domain fold / inflammasome
Function / homology
Function and homology information


regulation of mucus secretion / NLRP6 inflammasome complex assembly / neutrophil-mediated killing of gram-positive bacterium / NLRP6 inflammasome complex / positive regulation of interleukin-18-mediated signaling pathway / non-membrane-bounded organelle / lipoteichoic acid binding / host-mediated regulation of intestinal microbiota composition / vasopressin receptor activity / acute inflammatory response to antigenic stimulus ...regulation of mucus secretion / NLRP6 inflammasome complex assembly / neutrophil-mediated killing of gram-positive bacterium / NLRP6 inflammasome complex / positive regulation of interleukin-18-mediated signaling pathway / non-membrane-bounded organelle / lipoteichoic acid binding / host-mediated regulation of intestinal microbiota composition / vasopressin receptor activity / acute inflammatory response to antigenic stimulus / canonical inflammasome complex / acute inflammatory response / negative regulation of toll-like receptor signaling pathway / pattern recognition receptor activity / detection of maltose stimulus / maltose transport complex / pyroptotic inflammatory response / carbohydrate transport / necroptotic process / antiviral innate immune response / negative regulation of type II interferon production / carbohydrate transmembrane transporter activity / maltose binding / maltose transport / maltodextrin transmembrane transport / signaling adaptor activity / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / negative regulation of canonical NF-kappaB signal transduction / negative regulation of inflammatory response to antigenic stimulus / ATP-binding cassette (ABC) transporter complex / cell chemotaxis / molecular condensate scaffold activity / regulation of autophagy / lipopolysaccharide binding / peptide binding / response to bacterium / wound healing / protein homooligomerization / negative regulation of ERK1 and ERK2 cascade / positive regulation of inflammatory response / double-stranded RNA binding / regulation of inflammatory response / outer membrane-bounded periplasmic space / nuclear membrane / defense response to virus / periplasmic space / defense response to Gram-positive bacterium / DNA damage response / ATP binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
NACHT, LRR and PYD domains-containing protein, helical domain HD2 / NLRC4 helical domain HD2 / NOD2, winged helix domain / NOD2 winged helix domain / DAPIN domain / DAPIN domain profile. / PAAD/DAPIN/Pyrin domain / NACHT nucleoside triphosphatase / NACHT domain / NACHT-NTPase domain profile. ...NACHT, LRR and PYD domains-containing protein, helical domain HD2 / NLRC4 helical domain HD2 / NOD2, winged helix domain / NOD2 winged helix domain / DAPIN domain / DAPIN domain profile. / PAAD/DAPIN/Pyrin domain / NACHT nucleoside triphosphatase / NACHT domain / NACHT-NTPase domain profile. / PAAD/DAPIN/Pyrin domain / Leucine rich repeat, ribonuclease inhibitor type / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / Death-like domain superfamily / Leucine-rich repeat domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Maltose/maltodextrin-binding periplasmic protein / NACHT, LRR and PYD domains-containing protein 6
Similarity search - Component
Biological speciesEscherichia coli (E. coli)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.27 Å
AuthorsShen, C. / Fu, T.M. / Wu, H.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)Al124491 United States
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)HD087988 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2019
Title: Molecular mechanism for NLRP6 inflammasome assembly and activation.
Authors: Chen Shen / Alvin Lu / Wen Jun Xie / Jianbin Ruan / Roberto Negro / Edward H Egelman / Tian-Min Fu / Hao Wu /
Abstract: Inflammasomes are large protein complexes that trigger host defense in cells by activating inflammatory caspases for cytokine maturation and pyroptosis. NLRP6 is a sensor protein in the nucleotide- ...Inflammasomes are large protein complexes that trigger host defense in cells by activating inflammatory caspases for cytokine maturation and pyroptosis. NLRP6 is a sensor protein in the nucleotide-binding domain (NBD) and leucine-rich repeat (LRR)-containing (NLR) inflammasome family that has been shown to play multiple roles in regulating inflammation and host defenses. Despite the significance of the NLRP6 inflammasome, little is known about the molecular mechanism behind its assembly and activation. Here we present cryo-EM and crystal structures of NLRP6 pyrin domain (PYD). We show that NLRP6 PYD alone is able to self-assemble into filamentous structures accompanied by large conformational changes and can recruit the ASC adaptor using PYD-PYD interactions. Using molecular dynamics simulations, we identify the surface that the NLRP6 PYD filament uses to recruit ASC PYD. We further find that full-length NLRP6 assembles in a concentration-dependent manner into wider filaments with a PYD core surrounded by the NBD and the LRR domain. These findings provide a structural understanding of inflammasome assembly by NLRP6 and other members of the NLR family.
History
DepositionDec 13, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 23, 2019Provider: repository / Type: Initial release
Revision 1.1Feb 6, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Feb 20, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Maltose/maltodextrin-binding periplasmic protein, NACHT, LRR and PYD domains-containing protein 6 chimera
B: Maltose/maltodextrin-binding periplasmic protein, NACHT, LRR and PYD domains-containing protein 6 chimera


Theoretical massNumber of molelcules
Total (without water)104,7392
Polymers104,7392
Non-polymers00
Water9,170509
1
A: Maltose/maltodextrin-binding periplasmic protein, NACHT, LRR and PYD domains-containing protein 6 chimera


Theoretical massNumber of molelcules
Total (without water)52,3691
Polymers52,3691
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Maltose/maltodextrin-binding periplasmic protein, NACHT, LRR and PYD domains-containing protein 6 chimera


Theoretical massNumber of molelcules
Total (without water)52,3691
Polymers52,3691
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)38.283, 65.364, 102.362
Angle α, β, γ (deg.)95.63, 92.13, 106.59
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Maltose/maltodextrin-binding periplasmic protein, NACHT, LRR and PYD domains-containing protein 6 chimera / MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Angiotensin II/vasopressin ...MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Angiotensin II/vasopressin receptor / PYRIN-containing APAF1-like protein 5


Mass: 52369.285 Da / Num. of mol.: 2
Fragment: MBP (UNP residues 29-387) + PYD domain (UNP residues 14-106)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Homo sapiens (human)
Strain: K12 / Gene: malE, b4034, JW3994, NLRP6, NALP6, PYPAF5 / Production host: Escherichia coli (E. coli) / References: UniProt: P0AEX9, UniProt: P59044
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 509 / Source method: isolated from a natural source / Formula: H2O

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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: 2.33 Å3/Da / Density % sol: 47.14 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.2 M lithium sulfate, 0.1 M Bis-Tris, pH 6.5, 25% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 19, 2015
RadiationMonochromator: Cryo-cooled double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.27→101.63 Å / Num. obs: 43656 / % possible obs: 92.3 % / Redundancy: 7.3 % / Net I/σ(I): 10.5
Reflection shellResolution: 2.27→2.44 Å

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Processing

Software
NameVersionClassification
PHENIX(1.14_3211: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.27→101.63 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 2.03 / Phase error: 23.44
RfactorNum. reflection% reflection
Rfree0.2291 1984 4.88 %
Rwork0.1874 --
obs0.1895 40678 93.18 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.27→101.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6873 0 0 509 7382
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0027033
X-RAY DIFFRACTIONf_angle_d0.4939541
X-RAY DIFFRACTIONf_dihedral_angle_d13.6234231
X-RAY DIFFRACTIONf_chiral_restr0.041034
X-RAY DIFFRACTIONf_plane_restr0.0031246
Refinement TLS params.Method: refined / Origin x: -32.6922 Å / Origin y: 111.8891 Å / Origin z: 16.5558 Å
111213212223313233
T0.1543 Å2-0.0089 Å2-0.0098 Å2-0.1711 Å2-0.022 Å2--0.1923 Å2
L0.1948 °2-0.0325 °2-0.0484 °2-0.1292 °2-0.0813 °2--0.4029 °2
S-0.0032 Å °0.0006 Å °-0.0044 Å °-0.0032 Å °0.0397 Å °0.015 Å °0.0073 Å °0.0251 Å °-0.0317 Å °
Refinement TLS groupSelection details: all

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