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- PDB-7alv: Crystal Structure of NLRP3 NACHT domain in complex with a potent ... -

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Basic information

Entry
Database: PDB / ID: 7alv
TitleCrystal Structure of NLRP3 NACHT domain in complex with a potent inhibitor
ComponentsNACHT, LRR and PYD domains-containing protein 3
KeywordsIMMUNE SYSTEM / inflammasome
Function / homology
Function and homology information


small molecule sensor activity / detection of biotic stimulus / cysteine-type endopeptidase activator activity / phosphatidylinositol phosphate binding / positive regulation of T-helper 2 cell differentiation / NLRP3 inflammasome complex assembly / interphase microtubule organizing center / positive regulation of T-helper 2 cell cytokine production / positive regulation of type 2 immune response / NLRP3 inflammasome complex ...small molecule sensor activity / detection of biotic stimulus / cysteine-type endopeptidase activator activity / phosphatidylinositol phosphate binding / positive regulation of T-helper 2 cell differentiation / NLRP3 inflammasome complex assembly / interphase microtubule organizing center / positive regulation of T-helper 2 cell cytokine production / positive regulation of type 2 immune response / NLRP3 inflammasome complex / peptidoglycan binding / osmosensory signaling pathway / phosphatidylinositol-4-phosphate binding / negative regulation of non-canonical NF-kappaB signal transduction / pattern recognition receptor signaling pathway / negative regulation of interleukin-1 beta production / microtubule organizing center / negative regulation of NF-kappaB transcription factor activity / positive regulation of interleukin-4 production / pyroptotic inflammatory response / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / negative regulation of acute inflammatory response / The NLRP3 inflammasome / protein maturation / Purinergic signaling in leishmaniasis infection / signaling adaptor activity / molecular condensate scaffold activity / positive regulation of interleukin-1 beta production / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / protein homooligomerization / Cytoprotection by HMOX1 / Metalloprotease DUBs / cellular response to virus / ADP binding / defense response / negative regulation of inflammatory response / positive regulation of inflammatory response / positive regulation of non-canonical NF-kappaB signal transduction / SARS-CoV-1 activates/modulates innate immune responses / protein-macromolecule adaptor activity / positive regulation of NF-kappaB transcription factor activity / cellular response to lipopolysaccharide / DNA-binding transcription factor binding / sequence-specific DNA binding / molecular adaptor activity / inflammatory response / Golgi membrane / innate immune response / apoptotic process / SARS-CoV-2 activates/modulates innate and adaptive immune responses / endoplasmic reticulum / signal transduction / ATP hydrolysis activity / positive regulation of transcription by RNA polymerase II / mitochondrion / extracellular region / ATP binding / identical protein binding / membrane / nucleus / cytoplasm / cytosol
Similarity search - Function
NACHT-associated domain / Fish-specific NACHT associated domain / Fish-specific NACHT associated domain / 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-associated domain / Fish-specific NACHT associated domain / Fish-specific NACHT associated domain / 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 / Leucine Rich repeat / Death-like domain superfamily / Leucine-rich repeat / Leucine-rich repeat domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / Chem-RM5 / NACHT, LRR and PYD domains-containing protein 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.835 Å
AuthorsDekker, C. / Hinniger, A.
CitationJournal: J.Mol.Biol. / Year: 2021
Title: Crystal Structure of NLRP3 NACHT Domain With an Inhibitor Defines Mechanism of Inflammasome Inhibition.
Authors: Dekker, C. / Mattes, H. / Wright, M. / Boettcher, A. / Hinniger, A. / Hughes, N. / Kapps-Fouthier, S. / Eder, J. / Erbel, P. / Stiefl, N. / Mackay, A. / Farady, C.J.
History
DepositionOct 7, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 20, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 3, 2021Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Nov 17, 2021Group: Data collection / Database references / Category: citation / pdbx_database_proc / Item: _citation.journal_volume / _citation.title
Revision 1.3Jan 31, 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: NACHT, LRR and PYD domains-containing protein 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,0263
Polymers64,1561
Non-polymers8702
Water1448
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area740 Å2
ΔGint-7 kcal/mol
Surface area20670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)96.180, 96.180, 262.540
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122

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Components

#1: Protein NACHT, LRR and PYD domains-containing protein 3 / Angiotensin/vasopressin receptor AII/AVP-like / Caterpiller protein 1.1 / CLR1.1 / Cold-induced ...Angiotensin/vasopressin receptor AII/AVP-like / Caterpiller protein 1.1 / CLR1.1 / Cold-induced autoinflammatory syndrome 1 protein / Cryopyrin / PYRIN-containing APAF1-like protein 1


Mass: 64156.305 Da / Num. of mol.: 1 / Fragment: NACHT domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NLRP3, C1orf7, CIAS1, NALP3, PYPAF1 / Cell line (production host): Sf9 / Production host: unidentified baculovirus / References: UniProt: Q96P20
#2: Chemical ChemComp-RM5 / 1-[4-chloranyl-2,6-di(propan-2-yl)phenyl]-3-[4-(2-oxidanylpropan-2-yl)furan-2-yl]sulfonyl-urea


Mass: 442.957 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H27ClN2O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: ADP, energy-carrying molecule*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 8 / 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: 3.4 Å3/Da / Density % sol: 54.98 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 0.1 M Hepes pH 7.5, 1.4M SodiumCitrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 26, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.83→79.394 Å / Num. obs: 12189 / % possible obs: 100 % / Redundancy: 18.7 % / Biso Wilson estimate: 88.23 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.255 / Rpim(I) all: 0.06 / Rrim(I) all: 0.289 / Net I/σ(I): 12.9
Reflection shell

Num. unique obs: 609 / Diffraction-ID: 1

Resolution (Å)Redundancy (%)Mean I/σ(I) obsCC1/2Rpim(I) allRrim(I) all% possible all
2.835-3.147181.70.7060.552.36613.1
9.329-79.39415.452.40.9990.010.03899.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (20-MAY-2020)refinement
STARANISOdata scaling
PDB_EXTRACT3.2data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdbid 5irn, 4kxf

5irn

4kxf


Resolution: 2.835→79.39 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.853 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.474
RfactorNum. reflection% reflectionSelection details
Rfree0.2647 633 5.19 %RANDOM
Rwork0.2128 ---
obs0.2154 12189 68.2 %-
Displacement parametersBiso max: 209.02 Å2 / Biso mean: 83.37 Å2 / Biso min: 26.54 Å2
Baniso -1Baniso -2Baniso -3
1-1.4564 Å20 Å20 Å2
2--1.4564 Å20 Å2
3----2.9129 Å2
Refine analyzeLuzzati coordinate error obs: 0.43 Å
Refinement stepCycle: final / Resolution: 2.835→79.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3718 0 56 8 3782
Biso mean--55.05 42.99 -
Num. residues----472
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1315SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes650HARMONIC5
X-RAY DIFFRACTIONt_it3864HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion503SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2997SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3864HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg5232HARMONIC21
X-RAY DIFFRACTIONt_omega_torsion2.74
X-RAY DIFFRACTIONt_other_torsion20.01
LS refinement shellResolution: 2.835→3.09 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.3899 18 4.57 %
Rwork0.2651 376 -
obs--9.81 %
Refinement TLS params.Method: refined / Origin x: 14.3407 Å / Origin y: 34.7814 Å / Origin z: 133.901 Å
111213212223313233
T-0.2151 Å2-0.0799 Å20.0806 Å2--0.1823 Å2-0.0272 Å2---0.2008 Å2
L3.6413 °2-1.1572 °2-2.1833 °2-1.9311 °22.3965 °2--5.8919 °2
S-0.2009 Å °-0.0349 Å °-0.3912 Å °0.174 Å °-0.0394 Å °0.0488 Å °0.6819 Å °0.0951 Å °0.2403 Å °
Refinement TLS groupSelection details: { A|* }

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