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- PDB-3nf7: Structural basis for a new mechanism of inhibition of HIV integra... -

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Basic information

Entry
Database: PDB / ID: 3nf7
TitleStructural basis for a new mechanism of inhibition of HIV integrase identified by fragment screening and structure based design
ComponentsIntegrase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / INTEGRASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


nucleotidyltransferase activity / HIV-1 retropepsin / : / retroviral ribonuclease H / exoribonuclease H / : / exoribonuclease H activity / host multivesicular body / DNA integration / viral genome integration into host DNA ...nucleotidyltransferase activity / HIV-1 retropepsin / : / retroviral ribonuclease H / exoribonuclease H / : / exoribonuclease H activity / host multivesicular body / DNA integration / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency / viral penetration into host nucleus / RNA-directed DNA polymerase activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / RNA-DNA hybrid ribonuclease activity / endonuclease activity / viral nucleocapsid / DNA recombination / Hydrolases; Acting on ester bonds / DNA-directed DNA polymerase / nucleic acid binding / aspartic-type endopeptidase activity / DNA-directed DNA polymerase activity / symbiont entry into host cell / symbiont-mediated suppression of host gene expression / lipid binding / host cell nucleus / structural molecule activity / host cell plasma membrane / virion membrane / proteolysis / DNA binding / RNA binding / zinc ion binding / membrane
Similarity search - Function
Ribonuclease H-like superfamily/Ribonuclease H / Reverse transcriptase connection / Reverse transcriptase connection domain / Reverse transcriptase thumb / Reverse transcriptase thumb domain / Integrase Zinc binding domain / Zinc finger integrase-type profile. / Integrase-like, N-terminal / Integrase DNA binding domain / Integrase, C-terminal domain superfamily, retroviral ...Ribonuclease H-like superfamily/Ribonuclease H / Reverse transcriptase connection / Reverse transcriptase connection domain / Reverse transcriptase thumb / Reverse transcriptase thumb domain / Integrase Zinc binding domain / Zinc finger integrase-type profile. / Integrase-like, N-terminal / Integrase DNA binding domain / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain / Integrase, C-terminal, retroviral / Integrase DNA binding domain profile. / Immunodeficiency lentiviral matrix, N-terminal / gag gene protein p17 (matrix protein) / RNase H / Integrase core domain / Integrase, catalytic core / Integrase catalytic domain profile. / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Retropepsin-like catalytic domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Ribonuclease H domain / RNase H type-1 domain profile. / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Retrovirus capsid, C-terminal / Retroviral matrix protein / Retrovirus capsid, N-terminal / zinc finger / Zinc knuckle / Zinc finger, CCHC-type superfamily / Zinc finger, CCHC-type / Zinc finger CCHC-type profile. / Nucleotidyltransferase; domain 5 / Ribonuclease H superfamily / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Ribonuclease H-like superfamily / Reverse transcriptase/Diguanylate cyclase domain / DNA/RNA polymerase superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
ACETIC ACID / Chem-CIW / Gag-Pol polyprotein / Integrase
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsPeat, T.S. / Newman, J. / Deadman, J.J. / Rhodes, D.
CitationJournal: ANTIVIR.CHEM.CHEMOTHER. / Year: 2011
Title: Structural basis for a new mechanism of inhibition of HIV-1 integrase identified by fragment screening and structure-based design
Authors: Rhodes, D.I. / Peat, T.S. / Vandegraaff, N. / Jeevarajah, D. / Le, G. / Jones, E.D. / Smith, J.A. / Coates, J.A. / Winfield, L.J. / Thienthong, N. / Newman, J. / Lucent, D. / Ryan, J.H. / ...Authors: Rhodes, D.I. / Peat, T.S. / Vandegraaff, N. / Jeevarajah, D. / Le, G. / Jones, E.D. / Smith, J.A. / Coates, J.A. / Winfield, L.J. / Thienthong, N. / Newman, J. / Lucent, D. / Ryan, J.H. / Savage, G.P. / Francis, C.L. / Deadman, J.J.
History
DepositionJun 9, 2010Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Apr 27, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2May 2, 2012Group: Database references
Revision 1.3Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Integrase
B: Integrase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,28623
Polymers40,0892
Non-polymers2,19721
Water3,045169
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2790 Å2
ΔGint-17 kcal/mol
Surface area14260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.333, 71.333, 66.915
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number144
Space group name H-MP31
DetailsAT LEAST A DIMER IF NOT A TETRAMER IN THE CELL; SEEN AS A DIMER IN SOLUTION AND IN THE CRYSTAL

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Integrase /


Mass: 20044.672 Da / Num. of mol.: 2 / Fragment: catalytic domain, UNP residues 50-212 / Mutation: F185H, C56S, F139D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q76353, UniProt: P12497*PLUS

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Non-polymers , 5 types, 190 molecules

#2: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-ACY / ACETIC ACID / Acetic acid


Mass: 60.052 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H4O2
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-CIW / 5-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1,3-benzodioxole-4-carboxylic acid


Mass: 345.734 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H12ClNO5
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 169 / 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: 2.45 Å3/Da / Density % sol: 49.83 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.3
Details: 1.7M ammonium sulfate, 0.1M sodium acetate pH 5.3, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.95369 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 27, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95369 Å / Relative weight: 1
ReflectionResolution: 1.8→66.9 Å / Num. obs: 35320 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 2.7 / Redundancy: 5.6 % / Biso Wilson estimate: 23.9 Å2 / Rmerge(I) obs: 0.056
Reflection shellResolution: 1.8→1.9 Å / Redundancy: 5.7 % / Rmerge(I) obs: 0.269 / Mean I/σ(I) obs: 5.9 / Num. unique all: 5175 / % possible all: 100

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
REFMAC5.5.0102refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→35.67 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.941 / SU B: 1.883 / SU ML: 0.061 / Cross valid method: THROUGHOUT / ESU R Free: 0.11 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20748 1768 5 %RANDOM
Rwork0.16235 ---
all0.165 33527 --
obs0.16461 33527 99.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.172 Å2
Baniso -1Baniso -2Baniso -3
1-0.07 Å20.03 Å20 Å2
2--0.07 Å20 Å2
3----0.1 Å2
Refinement stepCycle: LAST / Resolution: 1.8→35.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2318 0 134 169 2621
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.030.0222696
X-RAY DIFFRACTIONr_angle_refined_deg2.4021.983699
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9025346
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.56225.315111
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.24415462
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.807158
X-RAY DIFFRACTIONr_chiral_restr0.2020.2406
X-RAY DIFFRACTIONr_gen_planes_refined0.0130.0212090
X-RAY DIFFRACTIONr_mcbond_it1.6441.51610
X-RAY DIFFRACTIONr_mcangle_it2.74622622
X-RAY DIFFRACTIONr_scbond_it3.69831086
X-RAY DIFFRACTIONr_scangle_it5.4254.51060
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.258 127 -
Rwork0.225 2510 -
obs--100 %

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