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- PDB-7djt: Human SARM1 inhibitory state bounded with inhibitor dHNN -

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Basic information

Entry
Database: PDB / ID: 7djt
TitleHuman SARM1 inhibitory state bounded with inhibitor dHNN
ComponentsNAD(+) hydrolase SARM1
KeywordsHYDROLASE / NAD(+) hydrolase
Function / homology
Function and homology information


negative regulation of MyD88-independent toll-like receptor signaling pathway / MyD88-independent TLR4 cascade / Toll Like Receptor 3 (TLR3) Cascade / NAD catabolic process / NAD+ nucleosidase activity / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / protein localization to mitochondrion / NAD+ nucleotidase, cyclic ADP-ribose generating / NADP+ nucleosidase activity / nervous system process ...negative regulation of MyD88-independent toll-like receptor signaling pathway / MyD88-independent TLR4 cascade / Toll Like Receptor 3 (TLR3) Cascade / NAD catabolic process / NAD+ nucleosidase activity / ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase / protein localization to mitochondrion / NAD+ nucleotidase, cyclic ADP-ribose generating / NADP+ nucleosidase activity / nervous system process / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / regulation of dendrite morphogenesis / response to axon injury / response to glucose / signaling adaptor activity / regulation of neuron apoptotic process / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / IKK complex recruitment mediated by RIP1 / nervous system development / microtubule / mitochondrial outer membrane / cell differentiation / axon / innate immune response / dendrite / synapse / 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 / Toll/interleukin-1 receptor homology (TIR) domain superfamily / 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 / Toll/interleukin-1 receptor homology (TIR) domain superfamily / 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-H8L / NAD(+) hydrolase SARM1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsCai, Y. / Zhang, H.
CitationJournal: Elife / Year: 2021
Title: Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate.
Authors: Wan Hua Li / Ke Huang / Yang Cai / Qian Wen Wang / Wen Jie Zhu / Yun Nan Hou / Sujing Wang / Sheng Cao / Zhi Ying Zhao / Xu Jie Xie / Yang Du / Chi-Sing Lee / Hon Cheung Lee / Hongmin Zhang / Yong Juan Zhao /
Abstract: SARM1 regulates axonal degeneration through its NAD-metabolizing activity and is a drug target for neurodegenerative disorders. We designed and synthesized fluorescent conjugates of styryl derivative ...SARM1 regulates axonal degeneration through its NAD-metabolizing activity and is a drug target for neurodegenerative disorders. We designed and synthesized fluorescent conjugates of styryl derivative with pyridine to serve as substrates of SARM1, which exhibited large red shifts after conversion. With the conjugates, SARM1 activation was visualized in live cells following elevation of endogenous NMN or treatment with a cell-permeant NMN-analog. In neurons, imaging documented mouse SARM1 activation preceded vincristine-induced axonal degeneration by hours. Library screening identified a derivative of nisoldipine (NSDP) as a covalent inhibitor of SARM1 that reacted with the cysteines, especially Cys311 in its ARM domain and blocked its NMN-activation, protecting axons from degeneration. The Cryo-EM structure showed that SARM1 was locked into an inactive conformation by the inhibitor, uncovering a potential neuroprotective mechanism of dihydropyridines.
History
DepositionNov 21, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 19, 2021Provider: repository / Type: Initial release
Revision 2.0Apr 5, 2023Group: Advisory / Atomic model ...Advisory / Atomic model / Author supporting evidence / Data collection / Database references / Derived calculations / Experimental preparation / Non-polymer description / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / database_2 / em_image_recording / em_specimen / em_vitrification / entity / entity_poly / entity_poly_seq / entity_src_gen / pdbx_entity_instance_feature / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_struct_assembly_gen / pdbx_struct_mod_residue / pdbx_validate_close_contact / pdbx_validate_main_chain_plane / pdbx_validate_rmsd_angle / struct_asym / struct_conn
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.group_PDB / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.label_seq_id / _atom_site.type_symbol / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_image_recording.detector_mode / _em_specimen.concentration / _em_vitrification.chamber_temperature / _em_vitrification.details / _em_vitrification.humidity / _em_vitrification.instrument / _entity_poly.nstd_monomer / _entity_poly.pdbx_seq_one_letter_code / _entity_poly_seq.mon_id / _entity_src_gen.gene_src_common_name / _pdbx_poly_seq_scheme.auth_mon_id / _pdbx_poly_seq_scheme.mon_id / _pdbx_poly_seq_scheme.pdb_mon_id / _pdbx_struct_assembly_gen.asym_id_list / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id
Revision 3.0Nov 15, 2023Group: Atomic model / Data collection / Non-polymer description
Category: atom_site / chem_comp ...atom_site / chem_comp / chem_comp_atom / chem_comp_bond / pdbx_validate_main_chain_plane / pdbx_validate_rmsd_angle
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id / _chem_comp.formula

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Structure visualization

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Assembly

Deposited unit
A: NAD(+) hydrolase SARM1
B: NAD(+) hydrolase SARM1
C: NAD(+) hydrolase SARM1
D: NAD(+) hydrolase SARM1
E: NAD(+) hydrolase SARM1
F: NAD(+) hydrolase SARM1
G: NAD(+) hydrolase SARM1
H: NAD(+) hydrolase SARM1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)616,25716
Polymers613,2778
Non-polymers2,9798
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: native gel electrophoresis
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
NAD(+) hydrolase SARM1 / hSARM1 / NADP(+) hydrolase SARM1 / Sterile alpha and Armadillo repeat protein / Sterile alpha and ...hSARM1 / NADP(+) hydrolase SARM1 / Sterile alpha and Armadillo repeat protein / Sterile alpha and TIR motif-containing protein 1 / Sterile alpha motif domain-containing protein 2 / SAM domain-containing protein 2 / Tir-1 homolog / HsTIR


Mass: 76659.656 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SARM1, KIAA0524, SAMD2, SARM / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
References: UniProt: Q6SZW1, ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase, Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds
#2: Chemical
ChemComp-H8L / O3-methyl O5-(2-methylpropyl) 2,6-dimethyl-4-[2-(oxidanylamino)phenyl]pyridine-3,5-dicarboxylate


Mass: 372.415 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C20H24N2O5
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human NAD(+) hydrolysis SARM1 / Type: CELL / Entity ID: #1 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293F
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaClSodium chloride1
2100 mMTrisTris1
31 mMEthylenediaminetetraacetic acidEDTAEthylenediaminetetraacetic acid1
SpecimenConc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Details: BLOT TIME: 4S BLOT FORCE: -2

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 130000 X / Calibrated magnification: 130000 X / Nominal defocus max: -800 nm / Calibrated defocus min: -2000 nm / Calibrated defocus max: -2500 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 1.28 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of real images: 2673
Image scansMovie frames/image: 39 / Used frames/image: 4-36

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
EM software
IDNameVersionCategory
2SerialEMimage acquisition
4RELION3.1CTF correction
9PHENIX1.16model refinement
10RELION3.1initial Euler assignment
11cisTEMbeta - 1.0.0final Euler assignment
12cisTEMbeta - 1.0.0classification
13cisTEMbeta - 1.0.03D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2655835
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 247454 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
RefinementHighest resolution: 2.8 Å
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00640776
ELECTRON MICROSCOPYf_angle_d0.91155120
ELECTRON MICROSCOPYf_dihedral_angle_d12.29524896
ELECTRON MICROSCOPYf_chiral_restr0.0536248
ELECTRON MICROSCOPYf_plane_restr0.0067168

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