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

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Basic information

Entry
Database: PDB / ID: 3nfa
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


HIV-1 retropepsin / : / retroviral ribonuclease H / exoribonuclease H / : / exoribonuclease H activity / host multivesicular body / DNA integration / RNA-directed DNA polymerase / viral genome integration into host DNA ...HIV-1 retropepsin / : / retroviral ribonuclease H / exoribonuclease H / : / exoribonuclease H activity / host multivesicular body / DNA integration / RNA-directed DNA polymerase / viral genome integration into host DNA / viral penetration into host nucleus / establishment of integrated proviral latency / RNA-directed DNA polymerase activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / RNA-DNA hybrid ribonuclease activity / viral nucleocapsid / endonuclease activity / DNA recombination / Hydrolases; Acting on ester bonds / DNA-directed DNA polymerase / 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-CBJ / Gag-Pol polyprotein / Integrase
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 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 10, 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)42,83119
Polymers40,0892
Non-polymers2,74217
Water1,928107
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2750 Å2
ΔGint-16 kcal/mol
Surface area14290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.474, 71.474, 66.833
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

#1: Protein Integrase /


Mass: 20044.672 Da / Num. of mol.: 2 / Fragment: catalytic domain, 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
#2: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-CBJ / 6-[(5-bromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)methyl]-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid


Mass: 418.195 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H12BrNO6
#4: Chemical
ChemComp-ACY / ACETIC ACID / Acetic acid


Mass: 60.052 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H4O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 107 / 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: 2.46 Å3/Da / Density % sol: 49.97 %
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: 0.98 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 15, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.95→19.7 Å / Num. all: 27854 / Num. obs: 27854 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 1.9 / Redundancy: 5.8 % / Biso Wilson estimate: 29.4 Å2 / Rmerge(I) obs: 0.046 / Net I/σ(I): 23.3
Reflection shellResolution: 1.95→2.06 Å / Redundancy: 5.8 % / Rmerge(I) obs: 0.401 / Mean I/σ(I) obs: 4.5 / Num. unique all: 4084 / % possible all: 100

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
REFMAC5.6.0062refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→18.91 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.951 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 1.9 / ESU R: 0.135 / ESU R Free: 0.13 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES: REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.20407 1407 5.1 %RANDOM
Rwork0.16201 ---
obs0.16418 26422 99.98 %-
all-26422 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 35.367 Å2
Baniso -1Baniso -2Baniso -3
1-0.1 Å20.05 Å20 Å2
2--0.1 Å20 Å2
3----0.16 Å2
Refinement stepCycle: LAST / Resolution: 1.95→18.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2318 0 164 107 2589
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0222687
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.2423690
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6495336
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.3625.278108
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.74315453
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.78158
X-RAY DIFFRACTIONr_chiral_restr0.140.2397
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212160
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.95→2 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.272 99 -
Rwork0.197 1977 -
all-2076 -
obs--100 %

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