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- PDB-2m9p: NMR structure of an inhibitor bound dengue NS3 protease -

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Basic information

Entry
Database: PDB / ID: 2m9p
TitleNMR structure of an inhibitor bound dengue NS3 protease
Components
  • Serine protease inhibitorSerpin
  • Serine protease subunit NS2B, Serine protease NS3
KeywordsHYDROLASE/HYDROLASE INHIBITOR / NS2B cofactor / covalent ligand / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


host cell mitochondrion / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / flavivirin / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / : / viral capsid / nucleoside-triphosphate phosphatase / protein complex oligomerization / double-stranded RNA binding ...host cell mitochondrion / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / flavivirin / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / : / viral capsid / nucleoside-triphosphate phosphatase / protein complex oligomerization / double-stranded RNA binding / monoatomic ion channel activity / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / clathrin-dependent endocytosis of virus by host cell / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA helicase activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / protein dimerization activity / RNA helicase / induction by virus of host autophagy / RNA-directed RNA polymerase / viral RNA genome replication / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / viral envelope / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / host cell nucleus / structural molecule activity / virion attachment to host cell / virion membrane / ATP hydrolysis activity / proteolysis / extracellular region / ATP binding / membrane / metal ion binding
Similarity search - Function
: / : / Flavivirus envelope glycoprotein E, stem/anchor domain / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2B / Flavivirus NS3 helicase, C-terminal helical domain / Genome polyprotein, Flavivirus / Flavivirus non-structural protein NS4A ...: / : / Flavivirus envelope glycoprotein E, stem/anchor domain / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2B / Flavivirus NS3 helicase, C-terminal helical domain / Genome polyprotein, Flavivirus / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus capsid protein C / Flavivirus non-structural protein NS4B / mRNA cap 0/1 methyltransferase / Flavivirus capsid protein C / Flavivirus non-structural protein NS4B / Flavivirus non-structural protein NS4A / Flavivirus NS2B domain profile. / mRNA cap 0 and cap 1 methyltransferase (EC 2.1.1.56 and EC 2.1.1.57) domain profile. / Flavivirus non-structural protein NS2A / Flavivirus non-structural protein NS2A / Flavivirus NS3, petidase S7 / Peptidase S7, Flavivirus NS3 serine protease / Flavivirus NS3 protease (NS3pro) domain profile. / Envelope glycoprotein M, flavivirus / Flavivirus envelope glycoprotein M / RNA-directed RNA polymerase, flavivirus / Flavivirus RNA-directed RNA polymerase, fingers and palm domains / Flavivirus non-structural Protein NS1 / Flavivirus non-structural protein NS1 / Envelope glycoprotein M superfamily, flavivirus / Flavivirus polyprotein propeptide / Flavivirus polyprotein propeptide superfamily / Flavivirus polyprotein propeptide / Flaviviral glycoprotein E, central domain, subdomain 1 / Flaviviral glycoprotein E, central domain, subdomain 2 / Flavivirus envelope glycoprotein E, Stem/Anchor domain / Flavivirus glycoprotein E, immunoglobulin-like domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain superfamily / Flavivirus glycoprotein, immunoglobulin-like domain / Flavivirus glycoprotein central and dimerisation domain / Flavivirus glycoprotein, central and dimerisation domains / Ribosomal RNA methyltransferase, FtsJ domain / FtsJ-like methyltransferase / Flavivirus/Alphavirus glycoprotein, immunoglobulin-like domain superfamily / Flavivirus glycoprotein, central and dimerisation domain superfamily / Flaviviral glycoprotein E, dimerisation domain / DEAD box, Flavivirus / Flavivirus DEAD domain / helicase superfamily c-terminal domain / Immunoglobulin E-set / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Serine protease inhibitor BEZ-NLE-LYS-ARG-M9P / Genome polyprotein
Similarity search - Component
Biological speciesDengue virus 2
MethodSOLUTION NMR / simulated annealing
Model detailslowest energy, model7
AuthorsGibbs, A. / Tounge, B. / Steele, R.
CitationJournal: To be Published
Title: NMR structure of an inhibitor bound dengue NS3 protease provides new insights into the NS2B NS3 ligand interactions
Authors: Gibbs, A. / Tounge, B. / Steele, R.
History
DepositionJun 18, 2013Deposition site: BMRB / Processing site: RCSB
Revision 1.0Jul 9, 2014Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: database_2 / pdbx_database_status ...database_2 / pdbx_database_status / pdbx_nmr_spectrometer / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_nmr_data / _pdbx_nmr_spectrometer.model / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr2_label_atom_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Serine protease subunit NS2B, Serine protease NS3
B: Serine protease inhibitor


Theoretical massNumber of molelcules
Total (without water)26,0762
Polymers26,0762
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area456.5 Å2
ΔGint-0.5 kcal/mol
Surface area736 Å2
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)10 / 200structures with the lowest energy
RepresentativeModel #1lowest energy

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Components

#1: Protein Serine protease subunit NS2B, Serine protease NS3 / / Flavivirin protease NS2B regulatory subunit / Non-structural protein 2B


Mass: 25343.268 Da / Num. of mol.: 1 / Fragment: UNP residues 1391-1440 and 1476-1648
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Dengue virus 2 / Strain: Thailand/0168/1979 / Production host: Escherichia coli (E. coli)
References: UniProt: P14337*PLUS, flavivirin, nucleoside-triphosphate phosphatase, RNA helicase
#2: Protein/peptide Serine protease inhibitor / Serpin


Type: Peptide-like / Class: Enzyme inhibitor / Mass: 732.860 Da / Num. of mol.: 1 / Source method: obtained synthetically / References: Serine protease inhibitor BEZ-NLE-LYS-ARG-M9P

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
Details: Dengue NS3: One of two observed ligand binding modes
NMR experiment
Conditions-IDExperiment-IDSolution-IDType
1112D 1H-15N HSQC
1213D HN(CA)CO
1313D HNCO
1413D CBCA(CO)NH
1513D HN(CA)CB
1613D 1H-15N NOESY
1713D 1H-13C NOESY
1813D (H)CCH-TOCSY
1913D CCH-TOCSY
11013D CCH-NOESY
11113D CNH-NOESY
11213D NCH-NOESY

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Sample preparation

DetailsContents: 0.8 mM [U-13C; U-15N; U-2H] protein, 0.8 mM [U-5% 13C; U-100% 15N] protein, 0.8 mM [U-13C; U-15N; U-2H];[1H-13C]-I(delta1)LVM protein, 95% H2O/5% D2O
Solvent system: 95% H2O/5% D2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
0.8 mMentity_1-1[U-13C; U-15N; U-2H]1
0.8 mMentity_1-2[U-5% 13C; U-100% 15N]1
0.8 mMentity_1-3[U-13C; U-15N; U-2H];[1H-13C]-I(delta1)LVM1
Sample conditionspH: 6.5 / Pressure: ambient / Temperature: 298 K

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NMR measurement

NMR spectrometerType: Bruker Avance / Manufacturer: Bruker / Model: AVANCE / Field strength: 800 MHz

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Processing

NMR software
NameDeveloperClassification
CNSBrunger, Adams, Clore, Gros, Nilges and Readrefinement
X-PLORBrungerstructure solution
AutoStructureHuang, Tejero, Powers and Montelionestructure solution
RefinementMethod: simulated annealing / Software ordinal: 1
NMR representativeSelection criteria: lowest energy
NMR ensembleConformer selection criteria: structures with the lowest energy
Conformers calculated total number: 200 / Conformers submitted total number: 10

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