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- PDB-9sfg: Crystal structure of NLRP3 in complex with inhibitor NP3-742 -

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Basic information

Entry
Database: PDB / ID: 9sfg
TitleCrystal structure of NLRP3 in complex with inhibitor NP3-742
ComponentsNACHT, LRR and PYD domains-containing protein 3
KeywordsIMMUNE SYSTEM / NLRP3 / Inhibitor
Function / homology
Function and homology information


detection of biotic stimulus / molecular sensor activity / phosphatidylinositol phosphate binding / positive regulation of T-helper 2 cell differentiation / positive regulation of T-helper 2 cell cytokine production / NLRP3 inflammasome complex assembly / interphase microtubule organizing center / positive regulation of type 2 immune response / NLRP3 inflammasome complex / cysteine-type endopeptidase activator activity ...detection of biotic stimulus / molecular sensor activity / phosphatidylinositol phosphate binding / positive regulation of T-helper 2 cell differentiation / positive regulation of T-helper 2 cell cytokine production / NLRP3 inflammasome complex assembly / interphase microtubule organizing center / positive regulation of type 2 immune response / NLRP3 inflammasome complex / cysteine-type endopeptidase activator activity / 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 / pyroptotic inflammatory response / positive regulation of interleukin-4 production / negative regulation of acute inflammatory response / microtubule organizing center / The NLRP3 inflammasome / Purinergic signaling in leishmaniasis infection / signaling adaptor activity / protein maturation / positive regulation of interleukin-1 beta production / molecular condensate scaffold activity / positive regulation of non-canonical NF-kappaB signal transduction / positive regulation of NF-kappaB transcription factor activity / defense response / Cytoprotection by HMOX1 / ADP binding / protein homooligomerization / cellular response to virus / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / negative regulation of inflammatory response / Metalloprotease DUBs / positive regulation of inflammatory response / SARS-CoV-1 activates/modulates innate immune responses / cellular response to lipopolysaccharide / regulation of inflammatory response / protein-macromolecule adaptor activity / molecular adaptor activity / DNA-binding transcription factor binding / sequence-specific DNA binding / inflammatory response / Golgi membrane / innate immune response / apoptotic process / SARS-CoV-2 activates/modulates innate and adaptive immune responses / endoplasmic reticulum / signal transduction / positive regulation of transcription by RNA polymerase II / ATP hydrolysis activity / mitochondrion / extracellular region / ATP binding / identical protein binding / nucleus / membrane / 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 / 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 / NACHT, LRR and PYD domains-containing protein 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsSrinivas, H.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Other private Switzerland
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of NP3-742: A Structurally Diverse NLRP3 Inhibitor Identified through an Unusual Phenol Replacement.
Authors: Velcicky, J. / Langlois, J.B. / Wright, M. / Janser, P. / Angst, D. / Arnold, C. / Beltz, K. / Brenneisen, S. / Dubois, C. / Dawson, J. / Fischer, C. / Gommermann, N. / Heizmann, A. / Ilic, ...Authors: Velcicky, J. / Langlois, J.B. / Wright, M. / Janser, P. / Angst, D. / Arnold, C. / Beltz, K. / Brenneisen, S. / Dubois, C. / Dawson, J. / Fischer, C. / Gommermann, N. / Heizmann, A. / Ilic, S. / Machauer, R. / Maschlej, M. / Monnerat, S. / Pflieger, D. / Ristov, J. / Rubert, J. / Schwalm, G. / Smith, D.R. / Srinivas, H. / Steiner, R. / Stojanovic, A. / Troxler, T. / Unterreiner, A. / Vangrevelinghe, E. / von Burg, N. / Wunderlich, J. / Farady, C.J. / Mackay, A.
History
DepositionAug 19, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 22, 2025Provider: repository / Type: Initial release

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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)64,9203
Polymers64,1561
Non-polymers7642
Water37821
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1480 Å2
ΔGint-7 kcal/mol
Surface area21050 Å2
Unit cell
Length a, b, c (Å)96.150, 96.150, 260.655
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Space group name HallP612(x,y,z+5/12)
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/6
#3: y,-x+y,z+5/6
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: x-y,-y,-z
#7: -x,-x+y,-z+2/3
#8: -x,-y,z+1/2
#9: y,x,-z+1/3
#10: -y,-x,-z+5/6
#11: -x+y,y,-z+1/2
#12: x,x-y,-z+1/6

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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 / 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-A1JNK / 5-methyl-~{N}-[(3~{R})-1-methylpiperidin-3-yl]-6-(2-methyl-1~{H}-pyrrolo[2,3-b]pyridin-6-yl)pyridazin-3-amine


Mass: 336.434 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H24N6 / 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 / Comment: ADP, energy-carrying molecule*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 21 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.71 Å3/Da / Density % sol: 54.62 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: protein: well = 1: 1 well: 1.94 M Ammonium citrate pH 7.0 protein: 7 mg/ml, 1mM inhibitor co-complex

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-3 / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 24, 2025
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.2→50 Å / Num. obs: 12355 / % possible obs: 100 % / Redundancy: 17.9 % / Biso Wilson estimate: 60.62 Å2 / CC1/2: 0.994 / Net I/σ(I): 6.5
Reflection shellResolution: 3.2→3.268 Å / Num. unique obs: 586 / CC1/2: 0.46

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Processing

Software
NameVersionClassification
PHENIX1.21.2_5419+SVNrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.2→48.07 Å / SU ML: 0.3948 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 24.0951
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2789 431 4.6 %
Rwork0.2112 8948 -
obs0.2143 9379 75.08 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 77.87 Å2
Refinement stepCycle: LAST / Resolution: 3.2→48.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3874 0 52 21 3947
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01124018
X-RAY DIFFRACTIONf_angle_d1.47195436
X-RAY DIFFRACTIONf_chiral_restr0.1006602
X-RAY DIFFRACTIONf_plane_restr0.007678
X-RAY DIFFRACTIONf_dihedral_angle_d18.62681444
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.2-3.660.3226680.2521411X-RAY DIFFRACTION36.79
3.66-4.610.28421480.21093396X-RAY DIFFRACTION86.19
4.61-48.070.26782150.20414141X-RAY DIFFRACTION99.93
Refinement TLS params.Method: refined / Origin x: -14.6430104606 Å / Origin y: -33.4883647508 Å / Origin z: 2.53098395893 Å
111213212223313233
T0.484517982356 Å20.0107938598009 Å2-0.0669768187973 Å2-0.466938173045 Å20.0436045784378 Å2--0.328486929481 Å2
L2.99978847412 °2-1.12429326691 °22.24105748482 °2-2.14702765275 °2-2.59420291561 °2--4.97646714186 °2
S-0.223624586827 Å °-0.0666978117148 Å °0.177073675417 Å °0.288935676142 Å °0.0863569001845 Å °0.0270534176829 Å °-0.752681456198 Å °-0.276799867993 Å °0.121556358131 Å °
Refinement TLS groupSelection details: all

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