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- PDB-5v8p: Small Molecule Inhibitor ABS-143 Bound to the Botulinum Neurotoxi... -

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Basic information

Entry
Database: PDB / ID: 5v8p
TitleSmall Molecule Inhibitor ABS-143 Bound to the Botulinum Neurotoxin Serotype A Light Chain
ComponentsBotulinum neurotoxin type A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / metalloprotease / drug design / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


host cell junction / negative regulation of neurotransmitter secretion / bontoxilysin / host cell presynaptic membrane / host cell cytoplasmic vesicle / host cell cytosol / protein transmembrane transporter activity / membrane => GO:0016020 / metalloendopeptidase activity / toxin activity ...host cell junction / negative regulation of neurotransmitter secretion / bontoxilysin / host cell presynaptic membrane / host cell cytoplasmic vesicle / host cell cytosol / protein transmembrane transporter activity / membrane => GO:0016020 / metalloendopeptidase activity / toxin activity / host cell plasma membrane / proteolysis / zinc ion binding / extracellular region / membrane
Similarity search - Function
Zincin-like / Metalloproteases ("zincins"), catalytic domain like / Clostridium neurotoxin, translocation / Clostridium neurotoxin, Translocation domain / Clostridium neurotoxin, translocation domain / Clostridial neurotoxin zinc protease / Botulinum/Tetanus toxin, catalytic chain / Clostridium neurotoxin, receptor-binding C-terminal / Clostridium neurotoxin, receptor binding N-terminal / Clostridium neurotoxin, C-terminal receptor binding ...Zincin-like / Metalloproteases ("zincins"), catalytic domain like / Clostridium neurotoxin, translocation / Clostridium neurotoxin, Translocation domain / Clostridium neurotoxin, translocation domain / Clostridial neurotoxin zinc protease / Botulinum/Tetanus toxin, catalytic chain / Clostridium neurotoxin, receptor-binding C-terminal / Clostridium neurotoxin, receptor binding N-terminal / Clostridium neurotoxin, C-terminal receptor binding / Clostridium neurotoxin, N-terminal receptor binding / Kunitz inhibitor STI-like superfamily / Neutral zinc metallopeptidases, zinc-binding region signature. / Concanavalin A-like lectin/glucanase domain superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-90G / Botulinum neurotoxin type A / Botulinum neurotoxin type A
Similarity search - Component
Biological speciesClostridium botulinum (bacteria)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.501 Å
AuthorsAllen, K.N. / Silvaggi, N.R.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)N01-AI30050 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)N01-AI080671 United States
CitationJournal: Toxicon / Year: 2017
Title: Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A.
Authors: Jacobson, A.R. / Adler, M. / Silvaggi, N.R. / Allen, K.N. / Smith, G.M. / Fredenburg, R.A. / Stein, R.L. / Park, J.B. / Feng, X. / Shoemaker, C.B. / Deshpande, S.S. / Goodnough, M.C. / ...Authors: Jacobson, A.R. / Adler, M. / Silvaggi, N.R. / Allen, K.N. / Smith, G.M. / Fredenburg, R.A. / Stein, R.L. / Park, J.B. / Feng, X. / Shoemaker, C.B. / Deshpande, S.S. / Goodnough, M.C. / Malizio, C.J. / Johnson, E.A. / Pellett, S. / Tepp, W.H. / Tzipori, S.
History
DepositionMar 22, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 26, 2017Provider: repository / Type: Initial release
Revision 1.1Aug 2, 2017Group: Author supporting evidence / Database references / Category: citation / pdbx_audit_support
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _pdbx_audit_support.funding_organization
Revision 1.2Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Botulinum neurotoxin type A
B: Botulinum neurotoxin type A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,3016
Polymers101,6352
Non-polymers6664
Water1,856103
1
A: Botulinum neurotoxin type A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,1503
Polymers50,8171
Non-polymers3332
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Botulinum neurotoxin type A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,1503
Polymers50,8171
Non-polymers3332
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)73.172, 67.327, 98.140
Angle α, β, γ (deg.)90.00, 105.60, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Botulinum neurotoxin type A / BoNT/A / Bontoxilysin-A / BOTOX


Mass: 50817.273 Da / Num. of mol.: 2 / Fragment: residues 1-424 / Mutation: P2Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Clostridium botulinum (bacteria) / Gene: botA, atx, bna / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P10845, UniProt: P0DPI1*PLUS, bontoxilysin
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: Zn
#3: Chemical ChemComp-90G / N-[3-(4-chlorophenyl)-1H-pyrazol-5-yl]-2-sulfanylacetamide


Mass: 267.735 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H10ClN3OS
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 103 / Source method: isolated from a natural source / Formula: H2O

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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: 2.28 Å3/Da / Density % sol: 46 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7
Details: Equal volumes of 10-12 mg/ml enzyme (50 mM Na2HPO4, 2 mM EDTA, pH 6.5) and crystallization buffer (10-15% polyethylene glycol [PEG] 2,000 monomethyl ester, 0.2-0.3 M K2HPO4, 0.1 M D,L-malic acid pH 7.0)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH2R / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: May 10, 2007 / Details: Osmic mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 31788 / % possible obs: 99.6 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.096 / Net I/σ(I): 16
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.616 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 10149 / % possible all: 99.7

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Processing

Software
NameVersionClassification
PHENIX(1.11_2567)refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3BON

3bon


Resolution: 2.501→18.334 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.61 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.252 1587 5 %
Rwork0.2022 --
obs0.2047 31759 99.39 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.501→18.334 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6414 0 36 103 6553
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0086594
X-RAY DIFFRACTIONf_angle_d1.0098905
X-RAY DIFFRACTIONf_dihedral_angle_d10.2983901
X-RAY DIFFRACTIONf_chiral_restr0.055967
X-RAY DIFFRACTIONf_plane_restr0.0081144
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5007-2.58120.31641380.27492612X-RAY DIFFRACTION95
2.5812-2.67320.32471430.27762733X-RAY DIFFRACTION100
2.6732-2.77990.31991440.26572743X-RAY DIFFRACTION100
2.7799-2.90590.29031440.26112719X-RAY DIFFRACTION100
2.9059-3.05840.28361440.24522753X-RAY DIFFRACTION100
3.0584-3.24910.30471430.23362729X-RAY DIFFRACTION100
3.2491-3.49830.2741450.20782750X-RAY DIFFRACTION100
3.4983-3.84750.25221460.19192760X-RAY DIFFRACTION100
3.8475-4.39750.2081450.16832762X-RAY DIFFRACTION100
4.3975-5.51520.22591460.16292779X-RAY DIFFRACTION100
5.5152-18.33450.21361490.18472832X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.15220.32690.0442.62630.73341.90890.05010.2780.1089-0.5694-0.02020.0702-0.5357-0.1926-0.09910.62060.07520.03510.44660.05540.3817-20.8353-5.3912-28.9913
21.71610.3450.52972.74960.14161.46820.03930.06990.0207-0.3912-0.12280.144-0.1382-0.07690.03020.40670.06820.00540.3893-0.02170.3605-26.1755-10.4521-27.4585
31.43130.28730.26432.35150.38460.89990.0228-0.30870.20950.0678-0.17210.5033-0.1474-0.3930.09820.35460.04620.03480.5537-0.02380.5339-34.0444-8.929-12.09
42.00890.46310.4252.61910.53361.74710.0822-0.105-0.1561-0.1474-0.10180.34080.1699-0.2750.06720.3447-0.0026-0.0180.39090.01090.4135-32.0297-21.3449-17.3065
53.1833-1.27820.09244.0083-0.23552.5341-0.472-0.27640.77480.55240.5386-0.646-0.18430.10030.03210.4717-0.0258-0.02130.4226-0.09630.526-14.38050.3185-0.9559
61.8952-0.06160.87392.7297-0.15441.62530.1710.1889-0.4101-0.5694-0.02290.14660.4370.1009-0.14440.5324-0.0362-0.03530.4019-0.050.417-13.6283-40.3938-30.1408
71.81320.49150.16062.2199-0.08071.92680.05650.1957-0.2253-0.4387-0.0833-0.45290.13730.23630.03220.4270.03680.08110.4139-0.03510.43140.3856-32.1047-28.3596
82.028-0.12190.51982.9145-0.5372.8210.1266-0.0518-0.10530.0528-0.2162-0.2863-0.11410.22750.07450.26090.02510.01540.3288-0.00440.3476-1.5171-28.3064-19.9708
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'B' and (resid -9 through 61 )
2X-RAY DIFFRACTION2chain 'B' and (resid 62 through 155 )
3X-RAY DIFFRACTION3chain 'B' and (resid 156 through 275 )
4X-RAY DIFFRACTION4chain 'B' and (resid 276 through 390 )
5X-RAY DIFFRACTION5chain 'B' and (resid 391 through 416 )
6X-RAY DIFFRACTION6chain 'A' and (resid -9 through 99 )
7X-RAY DIFFRACTION7chain 'A' and (resid 100 through 277 )
8X-RAY DIFFRACTION8chain 'A' and (resid 278 through 416 )

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