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- PDB-8zem: Crystal Structure of NLRP3 NACHT domain in complex with NP3-1 -

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Basic information

Entry
Database: PDB / ID: 8zem
TitleCrystal Structure of NLRP3 NACHT domain in complex with NP3-1
ComponentsNACHT, LRR and PYD domains-containing protein 3
KeywordsIMMUNE SYSTEM / NLRP3 / Inhibitor / NP3-1
Function / homology
Function and homology information


detection of biotic stimulus / molecular sensor activity / phosphatidylinositol phosphate binding / positive regulation of T-helper 2 cell differentiation / NLRP3 inflammasome complex assembly / positive regulation of T-helper 2 cell cytokine production / 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 / NLRP3 inflammasome complex assembly / positive regulation of T-helper 2 cell cytokine production / 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 / microtubule organizing center / negative regulation of acute inflammatory response / The NLRP3 inflammasome / Purinergic signaling in leishmaniasis infection / signaling adaptor activity / protein maturation / positive regulation of interleukin-1 beta production / molecular condensate scaffold activity / defense response / positive regulation of non-canonical NF-kappaB signal transduction / 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 / positive regulation of NF-kappaB transcription factor activity / SARS-CoV-1 activates/modulates innate immune responses / cellular response to lipopolysaccharide / regulation of inflammatory response / protein-macromolecule adaptor activity / DNA-binding transcription factor binding / molecular adaptor activity / 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 / NACHT nucleoside triphosphatase ...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 / NACHT nucleoside triphosphatase / NACHT domain / DAPIN domain profile. / NACHT-NTPase domain profile. / PAAD/DAPIN/Pyrin domain / 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: 3.32 Å
AuthorsShi, C. / Liu, Z.M.
Funding support1items
OrganizationGrant numberCountry
Other government
CitationJournal: J.Med.Chem. / Year: 2024
Title: Deep-Learning-Driven Discovery of SN3-1, a Potent NLRP3 Inhibitor with Therapeutic Potential for Inflammatory Diseases.
Authors: Shi, C. / Gao, T. / Lyu, W. / Qiang, B. / Chen, Y. / Chen, Q. / Zhang, L. / Liu, Z.
History
DepositionMay 6, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Oct 2, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _pdbx_entry_details.has_protein_modification

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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)65,1963
Polymers64,2431
Non-polymers9532
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance, The KD value is 6.9 nM
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area790 Å2
ΔGint-9 kcal/mol
Surface area21930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.246, 97.246, 256.792
Angle α, β, γ (deg.)90.00, 90.00, 120.00
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: 64243.383 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: unidentified baculovirus
References: UniProt: Q96P20, Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement
#2: Chemical ChemComp-A1D79 / 1-[5-[2,3-bis(chloranyl)phenyl]-2,3-dihydro-1~{H}-inden-4-yl]-3-[4-(2-oxidanylpropan-2-yl)thiophen-2-yl]sulfonyl-urea


Mass: 525.468 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22Cl2N2O4S2
#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
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: 2.73 Å3/Da / Density % sol: 54.91 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 23~25 % w/v Polyethylene glycol monomethyl ether 5,000 ;100 mM MES pH 6.3~6.7 ;200 mM Ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jan 25, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.32→84.22 Å / Num. obs: 6782 / % possible obs: 60.1 % / Redundancy: 36.5 % / CC1/2: 0.992 / Rmerge(I) obs: 0.77 / Rpim(I) all: 0.127 / Rrim(I) all: 0.78 / Net I/σ(I): 6
Reflection shellResolution: 3.32→3.797 Å / Rmerge(I) obs: 2.702 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 339 / CC1/2: 0.749 / Rpim(I) all: 0.468 / Rrim(I) all: 2.745 / % possible all: 9.5

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Processing

Software
NameVersionClassification
autoPROC1.1.7data reduction
STARANISO1.1.7data scaling
PHASER2.8.3phasing
REFMAC5.8.0267refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.32→84.22 Å / Cor.coef. Fo:Fc: 0.84 / Cor.coef. Fo:Fc free: 0.754 / SU B: 61.032 / SU ML: 0.839 / Cross valid method: THROUGHOUT / ESU R Free: 1.092 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.34679 348 5.1 %RANDOM
Rwork0.30474 ---
obs0.30687 6434 60.1 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 83.869 Å2
Baniso -1Baniso -2Baniso -3
1-0.54 Å20.27 Å20 Å2
2--0.54 Å2-0 Å2
3----1.74 Å2
Refinement stepCycle: 1 / Resolution: 3.32→84.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3910 0 60 0 3970
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0134059
X-RAY DIFFRACTIONr_bond_other_d0.0010.0153914
X-RAY DIFFRACTIONr_angle_refined_deg1.5071.6545465
X-RAY DIFFRACTIONr_angle_other_deg1.2661.5869005
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7285465
X-RAY DIFFRACTIONr_dihedral_angle_2_deg26.42521.606218
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.25715756
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.4881528
X-RAY DIFFRACTIONr_chiral_restr0.0710.2506
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.024417
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02975
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8878.9461884
X-RAY DIFFRACTIONr_mcbond_other0.8878.9451883
X-RAY DIFFRACTIONr_mcangle_it1.66713.3992341
X-RAY DIFFRACTIONr_mcangle_other1.66613.42342
X-RAY DIFFRACTIONr_scbond_it0.4368.9912175
X-RAY DIFFRACTIONr_scbond_other0.4368.9912175
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other0.91613.4373125
X-RAY DIFFRACTIONr_long_range_B_refined4.7618504
X-RAY DIFFRACTIONr_long_range_B_other4.768505
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.325→3.411 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.431 14 -
obs--1.74 %

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