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- PDB-7nai: Crystal structure of the TIR domain from human SARM1 in complex w... -

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Basic information

Entry
Database: PDB / ID: 7nai
TitleCrystal structure of the TIR domain from human SARM1 in complex with 3AD
ComponentsSterile alpha and TIR motif-containing protein 1
KeywordsHYDROLASE / NADase / Axon degeneration
Function / homology
Function and homology information


negative regulation of MyD88-independent toll-like receptor signaling pathway / Toll Like Receptor 3 (TLR3) Cascade / MyD88-independent TLR4 cascade / NAD catabolic process / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD+ nucleotidase, cyclic ADP-ribose generating / NAD(P)+ nucleosidase activity / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / NAD+ nucleosidase activity / signaling adaptor activity ...negative regulation of MyD88-independent toll-like receptor signaling pathway / Toll Like Receptor 3 (TLR3) Cascade / MyD88-independent TLR4 cascade / NAD catabolic process / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / NAD+ nucleotidase, cyclic ADP-ribose generating / NAD(P)+ nucleosidase activity / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / NAD+ nucleosidase activity / signaling adaptor activity / regulation of dendrite morphogenesis / extrinsic component of mitochondrial outer membrane / regulation of neuron death / response to axon injury / TRAF6-mediated induction of TAK1 complex within TLR4 complex / response to glucose / Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon / IKK complex recruitment mediated by RIP1 / positive regulation of neuron death / nervous system development / microtubule / regulation of apoptotic process / cell differentiation / axon / synapse / dendrite / innate immune response / signal transduction / mitochondrion / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Sterile alpha and TIR motif-containing protein 1 / TIR domain / Toll - interleukin 1 - resistance / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain superfamily / Toll/interleukin-1 receptor homology (TIR) domain / SAM domain (Sterile alpha motif) / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain ...Sterile alpha and TIR motif-containing protein 1 / TIR domain / Toll - interleukin 1 - resistance / TIR domain profile. / Toll/interleukin-1 receptor homology (TIR) domain superfamily / Toll/interleukin-1 receptor homology (TIR) domain / SAM domain (Sterile alpha motif) / SAM domain profile. / Sterile alpha motif. / Sterile alpha motif domain / Sterile alpha motif/pointed domain superfamily / Armadillo-like helical / Armadillo-type fold
Similarity search - Domain/homology
Chem-1O4 / NAD(+) hydrolase SARM1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.74 Å
AuthorsShi, Y. / Ve, T.
Funding support Australia, 2items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia) Australia
Australian Research Council (ARC) Australia
CitationJournal: Mol Cell / Year: 2022
Title: Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules.
Authors: Yun Shi / Philip S Kerry / Jeffrey D Nanson / Todd Bosanac / Yo Sasaki / Raul Krauss / Forhad K Saikot / Sarah E Adams / Tamim Mosaiab / Veronika Masic / Xianrong Mao / Faith Rose / Eduardo ...Authors: Yun Shi / Philip S Kerry / Jeffrey D Nanson / Todd Bosanac / Yo Sasaki / Raul Krauss / Forhad K Saikot / Sarah E Adams / Tamim Mosaiab / Veronika Masic / Xianrong Mao / Faith Rose / Eduardo Vasquez / Marieke Furrer / Katie Cunnea / Andrew Brearley / Weixi Gu / Zhenyao Luo / Lou Brillault / Michael J Landsberg / Aaron DiAntonio / Bostjan Kobe / Jeffrey Milbrandt / Robert O Hughes / Thomas Ve /
Abstract: The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and a therapeutic target for several neurodegenerative conditions. We show that a potent SARM1 ...The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and a therapeutic target for several neurodegenerative conditions. We show that a potent SARM1 inhibitor undergoes base exchange with the nicotinamide moiety of nicotinamide adenine dinucleotide (NAD) to produce the bona fide inhibitor 1AD. We report structures of SARM1 in complex with 1AD, NAD mimetics and the allosteric activator nicotinamide mononucleotide (NMN). NMN binding triggers reorientation of the armadillo repeat (ARM) domains, which disrupts ARM:TIR interactions and leads to formation of a two-stranded TIR domain assembly. The active site spans two molecules in these assemblies, explaining the requirement of TIR domain self-association for NADase activity and axon degeneration. Our results reveal the mechanisms of SARM1 activation and substrate binding, providing rational avenues for the design of new therapeutics targeting SARM1.
History
DepositionJun 21, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 23, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 6, 2022Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2May 18, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Sterile alpha and TIR motif-containing protein 1
B: Sterile alpha and TIR motif-containing protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0404
Polymers32,6672
Non-polymers1,3732
Water2,936163
1
A: Sterile alpha and TIR motif-containing protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,0202
Polymers16,3341
Non-polymers6861
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Sterile alpha and TIR motif-containing protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,0202
Polymers16,3341
Non-polymers6861
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.192, 116.779, 33.016
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z

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Components

#1: Protein Sterile alpha and TIR motif-containing protein 1 / Sterile alpha and Armadillo repeat protein / Sterile alpha motif domain-containing protein 2 / SAM ...Sterile alpha and Armadillo repeat protein / Sterile alpha motif domain-containing protein 2 / SAM domain-containing protein 2 / Tir-1 homolog


Mass: 16333.703 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SARM1, KIAA0524, SAMD2, SARM / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q6SZW1
#2: Chemical ChemComp-1O4 / [[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{R},3~{S},4~{R},5~{R})-5-(8-azanylisoquinolin-2-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl hydrogen phosphate


Mass: 686.482 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H30N7O13P2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 163 / 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: 2.54 Å3/Da / Density % sol: 51.64 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1 M Bis-Tris propane pH 7.0, 0.2 M potassium thiocyanate, and 10% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 22, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.74→48.34 Å / Num. obs: 35061 / % possible obs: 99.8 % / Redundancy: 6.7 % / Biso Wilson estimate: 19.48 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.058 / Rpim(I) all: 0.024 / Rrim(I) all: 0.063 / Net I/σ(I): 14.4
Reflection shellResolution: 1.74→1.77 Å / Rmerge(I) obs: 0.417 / Mean I/σ(I) obs: 3 / Num. unique obs: 1814 / CC1/2: 0.952 / Rpim(I) all: 0.173 / Rrim(I) all: 0.453

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6o0r
Resolution: 1.74→43.1 Å / SU ML: 0.1798 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 18.7379
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.197 2000 5.72 %
Rwork0.1657 32995 -
obs0.1675 34995 99.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25 Å2
Refinement stepCycle: LAST / Resolution: 1.74→43.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2244 0 92 163 2499
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092451
X-RAY DIFFRACTIONf_angle_d13343
X-RAY DIFFRACTIONf_chiral_restr0.058369
X-RAY DIFFRACTIONf_plane_restr0.0093474
X-RAY DIFFRACTIONf_dihedral_angle_d11.1508951
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.74-1.780.23651340.1962222X-RAY DIFFRACTION97.36
1.78-1.830.20881430.17832351X-RAY DIFFRACTION99.92
1.83-1.890.25381400.20392291X-RAY DIFFRACTION100
1.89-1.950.27831420.18842350X-RAY DIFFRACTION99.96
1.95-2.020.18561400.17312309X-RAY DIFFRACTION99.92
2.02-2.10.19021420.14792357X-RAY DIFFRACTION99.84
2.1-2.190.21781420.15332332X-RAY DIFFRACTION100
2.19-2.310.18671410.15882329X-RAY DIFFRACTION99.96
2.31-2.450.2121410.16952341X-RAY DIFFRACTION99.96
2.45-2.640.19291440.16212366X-RAY DIFFRACTION100
2.64-2.910.17971440.16112369X-RAY DIFFRACTION99.96
2.91-3.330.20531450.16742408X-RAY DIFFRACTION99.84
3.33-4.190.17621480.15042425X-RAY DIFFRACTION100
4.2-43.10.18971540.17362545X-RAY DIFFRACTION99.67

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