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- PDB-3zsz: Small molecule inhibitors of the LEDGF site of HIV type 1 integra... -

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Basic information

Entry
Database: PDB / ID: 3zsz
TitleSmall molecule inhibitors of the LEDGF site of HIV type 1 integrase identified by fragment screening and structure based drug design
ComponentsINTEGRASE
KeywordsTRANSFERASE / AIDS
Function / homology
Function and homology information


HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / 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 ...HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / 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 / symbiont-mediated suppression of host gene expression / RNA stem-loop binding / RNA-directed DNA polymerase activity / RNA-DNA hybrid ribonuclease activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / host cell / viral nucleocapsid / endonuclease activity / DNA recombination / DNA-directed DNA polymerase / Hydrolases; Acting on ester bonds / aspartic-type endopeptidase activity / DNA-directed DNA polymerase activity / symbiont entry into host cell / viral translational frameshifting / lipid binding / host cell nucleus / host cell plasma membrane / structural molecule activity / virion membrane / proteolysis / DNA 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. / Retropepsin-like catalytic domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / RNase H type-1 domain profile. / Ribonuclease H domain / Reverse transcriptase domain / Reverse transcriptase (RNA-dependent DNA polymerase) / 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 / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Ribonuclease H superfamily / Ribonuclease H-like superfamily / Reverse transcriptase/Diguanylate cyclase domain / DNA/RNA polymerase superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
ACETATE ION / Chem-OM2 / Gag-Pol polyprotein / Integrase
Similarity search - Component
Biological speciesHUMAN IMMUNODEFICIENCY VIRUS
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsPeat, T.S. / Newman, J. / Rhodes, D.I. / Vandergraaff, N. / Le, G. / Jones, E.D. / Smith, J.A. / Coates, J.A.V. / Thienthong, N. / Dolezal, O. ...Peat, T.S. / Newman, J. / Rhodes, D.I. / Vandergraaff, N. / Le, G. / Jones, E.D. / Smith, J.A. / Coates, J.A.V. / Thienthong, N. / Dolezal, O. / Ryan, J.H. / Savage, G.P. / Francis, C.L. / Deadman, J.J.
Citation
Journal: Plos One / Year: 2012
Title: Small Molecule Inhibitors of the Ledgf Site of Human Immunodeficiency Virus Integrase Identified by Fragment Screening and Structure Based Design.
Authors: Peat, T.S. / Rhodes, D.I. / Vandegraaff, N. / Le, G. / Smith, J.A. / Clark, L.J. / Jones, E.D. / Coates, J.A.V. / Thienthong, N. / Newman, J. / Dolezal, O. / Mulder, R. / Ryan, J.H. / ...Authors: Peat, T.S. / Rhodes, D.I. / Vandegraaff, N. / Le, G. / Smith, J.A. / Clark, L.J. / Jones, E.D. / Coates, J.A.V. / Thienthong, N. / Newman, J. / Dolezal, O. / Mulder, R. / Ryan, J.H. / Savage, G.P. / Francis, C.L. / Deadman, J.J.
#1: Journal: 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
DepositionJul 1, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 11, 2012Provider: repository / Type: Initial release
Revision 1.1Aug 1, 2012Group: Database references / Structure summary
Revision 1.2Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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

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Assembly

Deposited unit
A: INTEGRASE
B: INTEGRASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,49816
Polymers36,7922
Non-polymers1,70614
Water1,72996
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5910 Å2
ΔGint-105 kcal/mol
Surface area13560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.475, 71.475, 66.453
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number144
Space group name H-MP31

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein INTEGRASE


Mass: 18395.842 Da / Num. of mol.: 2 / Fragment: CORE CATALYTIC DOMAIN, RESIDUES 56-212 / Mutation: YES
Source method: isolated from a genetically manipulated source
Details: INHIBITOR BOUND TO LEDGF BINDING SITE / Source: (gene. exp.) HUMAN IMMUNODEFICIENCY VIRUS / Strain: TYPE 1 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21
References: UniProt: Q76353, UniProt: P12497*PLUS, Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases

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Non-polymers , 5 types, 110 molecules

#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical ChemComp-OM2 / (R)-[2-[[(2S)-BUTAN-2-YL]CARBAMOYL]PHENYL]METHYL-[(4-CARBOXY-1,3-BENZODIOXOL-5-YL)METHYL]-METHYL-AZANIUM


Mass: 399.460 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H27N2O5
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 96 / Source method: isolated from a natural source / Formula: H2O

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Details

Compound detailsENGINEERED RESIDUE IN CHAIN A, CYS 56 TO SER ENGINEERED RESIDUE IN CHAIN A, PHE 139 TO ASP ...ENGINEERED RESIDUE IN CHAIN A, CYS 56 TO SER ENGINEERED RESIDUE IN CHAIN A, PHE 139 TO ASP ENGINEERED RESIDUE IN CHAIN A, PHE 185 TO HIS ENGINEERED RESIDUE IN CHAIN B, CYS 56 TO SER ENGINEERED RESIDUE IN CHAIN B, PHE 139 TO ASP ENGINEERED RESIDUE IN CHAIN B, PHE 185 TO HIS
Nonpolymer detailsOM2 (R)-[2-[[(2S)-BUTAN-2-YL]CARBAMOYL]PHENYL] METHYL-[(4-CARBOXY-1,3-BENZODIOXOL-5-YL)METHYL]- ...OM2 (R)-[2-[[(2S)-BUTAN-2-YL]CARBAMOYL]PHENYL] METHYL-[(4-CARBOXY-1,3-BENZODIOXOL-5-YL)METHYL]- METHYL-AZANIUM IS AN ANALOGUE OF 3-BENZODIOXOLE-4- CARBOXYLIC ACID.

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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: 50 % / Description: NONE
Crystal growpH: 5.5
Details: THE PROTEIN WAS CONCENTRATED TO 5.5 MG/ML IN 40 MM TRIS PH 8.0, 250 MM NACL, 30 MM MGCL2, 5 MM DTT AND SET UP IN A 1:1 RATIO WITH 1.6 TO 2.0 M AMMONIUM SULFATE, 100 MM SODIUM ACETATE BUFFER PH 5.0 TO 5.5.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX1 / Wavelength: 0.96
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: Jul 29, 2009 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96 Å / Relative weight: 1
ReflectionResolution: 2→45.3 Å / Num. obs: 25674 / % possible obs: 100 % / Observed criterion σ(I): 1 / Redundancy: 5.6 % / Biso Wilson estimate: 27.12 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 16.4
Reflection shellResolution: 2→2.11 Å / Redundancy: 5.6 % / Rmerge(I) obs: 0.55 / Mean I/σ(I) obs: 3 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3NF7

3nf7


Resolution: 2→31.48 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.936 / SU B: 3.773 / SU ML: 0.107 / Cross valid method: THROUGHOUT / ESU R: 0.165 / ESU R Free: 0.148 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.22221 1303 5.1 %RANDOM
Rwork0.18657 ---
obs0.18842 24345 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.833 Å2
Baniso -1Baniso -2Baniso -3
1-0.18 Å20.09 Å20 Å2
2--0.18 Å20 Å2
3----0.27 Å2
Refinement stepCycle: LAST / Resolution: 2→31.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2318 0 109 96 2523
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0222573
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6181.9753514
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0365328
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.37125.37108
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.77915445
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.892158
X-RAY DIFFRACTIONr_chiral_restr0.1010.2391
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021978
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2360.21195
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3010.21723
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1540.2127
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1850.258
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0760.27
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.3631.51617
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.79522493
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.58831144
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.6784.51004
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.283 102 -
Rwork0.235 1767 -
obs--100 %

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