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- PDB-8ri2: Crystal structure of NLRP3 in complex with inhibitor NP3-562 -

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Basic information

Entry
Database: PDB / ID: 8ri2
TitleCrystal structure of NLRP3 in complex with inhibitor NP3-562
ComponentsNACHT, LRR and PYD domains-containing protein 3
KeywordsIMMUNE SYSTEM / inflammasome / inhibitor / NLRP3 / NALP3
Function / homology
Function and homology information


molecular 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 / NLRP3 inflammasome complex / positive regulation of type 2 immune response ...molecular 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 / NLRP3 inflammasome complex / positive regulation of type 2 immune response / osmosensory signaling pathway / peptidoglycan binding / phosphatidylinositol-4-phosphate binding / negative regulation of non-canonical NF-kappaB signal transduction / microtubule organizing center / pattern recognition receptor signaling pathway / negative regulation of interleukin-1 beta production / positive regulation of interleukin-4 production / pyroptotic inflammatory response / negative regulation of acute inflammatory response / The NLRP3 inflammasome / protein maturation / Purinergic signaling in leishmaniasis infection / signaling adaptor activity / positive regulation of interleukin-1 beta production / ADP binding / molecular condensate scaffold activity / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / protein homooligomerization / Cytoprotection by HMOX1 / cellular response to virus / Metalloprotease DUBs / 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 / positive regulation of NF-kappaB transcription factor activity / protein-macromolecule adaptor 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 / signal transduction / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / ATP hydrolysis activity / mitochondrion / extracellular region / ATP binding / identical protein binding / membrane / nucleus / cytosol / cytoplasm
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. ...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 / PAAD/DAPIN/Pyrin domain / NACHT nucleoside triphosphatase / NACHT domain / NACHT-NTPase domain profile. / 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
Chem-A1H02 / ADENOSINE-5'-DIPHOSPHATE / NACHT, LRR and PYD domains-containing protein 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsDekker, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of Potent, Orally Bioavailable, Tricyclic NLRP3 Inhibitors.
Authors: Velcicky, J. / Janser, P. / Gommermann, N. / Brenneisen, S. / Ilic, S. / Vangrevelinghe, E. / Stiefl, N. / Boettcher, A. / Arnold, C. / Malinverni, C. / Dawson, J. / Murgasova, R. / ...Authors: Velcicky, J. / Janser, P. / Gommermann, N. / Brenneisen, S. / Ilic, S. / Vangrevelinghe, E. / Stiefl, N. / Boettcher, A. / Arnold, C. / Malinverni, C. / Dawson, J. / Murgasova, R. / Desrayaud, S. / Beltz, K. / Hinniger, A. / Dekker, C. / Farady, C.J. / Mackay, A.
History
DepositionDec 18, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 17, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: 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

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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)65,0213
Polymers64,1561
Non-polymers8652
Water1,44180
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1620 Å2
ΔGint-8 kcal/mol
Surface area21020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)96.238, 96.238, 267.973
Angle α, β, γ (deg.)90, 90, 120
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
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: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q96P20, Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement
#2: Chemical ChemComp-A1H02 / 2-[4-chloranyl-9-oxidanylidene-12-(2-oxidanylpropan-2-yl)-5-thia-1,10,11-triazatricyclo[6.4.0.0^{2,6}]dodeca-2(6),3,7,11-tetraen-10-yl]-~{N}-[(3~{R})-1-methylpiperidin-3-yl]ethanamide


Mass: 437.944 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H24ClN5O3S / 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.: 80 / 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: 2.79 Å3/Da / Density % sol: 55.94 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7
Details: protein: well = 1: 1 well: 1.94 M Ammonium citrate pH 7.0 protein: 7 mg/ml protein copurified with 1 uM inhibitor

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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: Nov 16, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→83.34 Å / Num. obs: 18959 / % possible obs: 100 % / Redundancy: 19.1 % / Biso Wilson estimate: 65.9 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.33 / Rrim(I) all: 0.34 / Rsym value: 0.33 / Net I/σ(I): 11.7
Reflection shellResolution: 2.8→2.87 Å / Redundancy: 18.1 % / Rmerge(I) obs: 4.6 / Mean I/σ(I) obs: 0.8 / Num. unique obs: 1359 / CC1/2: 0.48 / Rrim(I) all: 4.73 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
XDS2015data reduction
XSCALE2015data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→79.58 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.932 / SU R Cruickshank DPI: 0.737 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.915 / SU Rfree Blow DPI: 0.351 / SU Rfree Cruickshank DPI: 0.346
RfactorNum. reflection% reflectionSelection details
Rfree0.2702 948 5 %RANDOM
Rwork0.2242 ---
obs0.2265 18959 100 %-
Displacement parametersBiso mean: 84.07 Å2
Baniso -1Baniso -2Baniso -3
1-0.6338 Å20 Å20 Å2
2--0.6338 Å20 Å2
3----1.2676 Å2
Refine analyzeLuzzati coordinate error obs: 0.41 Å
Refinement stepCycle: LAST / Resolution: 2.8→79.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3868 0 56 80 4004
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0074026HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.865462HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1392SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes684HARMONIC5
X-RAY DIFFRACTIONt_it4014HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion519SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3125SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.5
X-RAY DIFFRACTIONt_other_torsion20.59
LS refinement shellResolution: 2.8→2.82 Å
RfactorNum. reflection% reflection
Rfree0.3767 20 -
Rwork0.3632 --
obs0.3638 404 100 %
Refinement TLS params.Origin x: 13.7755 Å / Origin y: 33.7997 Å / Origin z: 136.343 Å
111213212223313233
T-0.112 Å2-0.0316 Å20.0265 Å2--0.1999 Å2-0.0026 Å2---0.1418 Å2
L2.7284 °2-0.7619 °2-0.9634 °2-0.8365 °21.5076 °2--4.4262 °2
S-0.0489 Å °0.1923 Å °0.5985 Å °0.1923 Å °0.0193 Å °0.1323 Å °0.5985 Å °0.1323 Å °0.0296 Å °
Refinement TLS groupSelection details: { A|* }

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