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- PDB-6um8: HIV Integrase in complex with Compound-14 -

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Basic information

Entry
Database: PDB / ID: 6um8
TitleHIV Integrase in complex with Compound-14
ComponentsIntegrase
KeywordsTRANSFERASE / Hydrolase / DNA Integration / AIDS / RNASEH / LEDGF / ENDONUCLEASE / HIV-1 integrase
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
DI(HYDROXYETHYL)ETHER / Chem-QCG / Gag-Pol polyprotein / Integrase
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.33 Å
AuthorsKhan, J.A. / Kish, K.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV-1 Integrase Inhibitors.
Authors: Li, G. / Meanwell, N.A. / Krystal, M.R. / Langley, D.R. / Naidu, B.N. / Sivaprakasam, P. / Lewis, H. / Kish, K. / Khan, J.A. / Ng, A. / Trainor, G.L. / Cianci, C. / Dicker, I.B. / Walker, M. ...Authors: Li, G. / Meanwell, N.A. / Krystal, M.R. / Langley, D.R. / Naidu, B.N. / Sivaprakasam, P. / Lewis, H. / Kish, K. / Khan, J.A. / Ng, A. / Trainor, G.L. / Cianci, C. / Dicker, I.B. / Walker, M.A. / Lin, Z. / Protack, T. / Discotto, L. / Jenkins, S. / Gerritz, S.W. / Pendri, A.
History
DepositionOct 9, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 4, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 25, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)38,99216
Polymers36,2432
Non-polymers2,74914
Water2,432135
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3470 Å2
ΔGint-17 kcal/mol
Surface area12310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)164.626, 164.626, 164.626
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number212
Space group name H-MP4332

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Integrase


Mass: 18121.600 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Plasmid: pET15b / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: Q76353, UniProt: P12497*PLUS

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Non-polymers , 5 types, 149 molecules

#2: Chemical
ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


Mass: 238.278 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#4: Chemical ChemComp-QCG / (2S)-tert-butoxy[7-(8-fluoro-5-methyl-3,4-dihydro-2H-1-benzopyran-6-yl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl]acetic acid


Mass: 503.565 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H30FN3O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 135 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 5.13 Å3/Da / Density % sol: 76.02 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 2.0 M ammonium sulfate and 100 mM citric acid pH 3.5
PH range: 3.5?

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 27, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.33→164.51 Å / Num. obs: 33296 / % possible obs: 100 % / Redundancy: 38.5 % / Biso Wilson estimate: 62.83 Å2 / Rsym value: 0.092 / Net I/σ(I): 42.2
Reflection shellResolution: 8.97→164.51 Å / Redundancy: 29.9 % / Mean I/σ(I) obs: 79.3 / Num. unique obs: 18666 / Rsym value: 0.043 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6NCJ

6ncj


Resolution: 2.33→116.41 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.938 / SU R Cruickshank DPI: 0.15 / Cross valid method: NONE / σ(F): 0 / SU R Blow DPI: 0.155 / SU Rfree Blow DPI: 0.143 / SU Rfree Cruickshank DPI: 0.14
RfactorNum. reflection% reflectionSelection details
Rfree0.22 1620 4.87 %RANDOM
Rwork0.196 ---
obs0.198 33296 99.9 %-
Displacement parametersBiso max: 155.78 Å2 / Biso mean: 62.57 Å2 / Biso min: 35.34 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 2.33→116.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2135 0 173 135 2443
Biso mean--79.42 70.21 -
Num. residues----280
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d846SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes466HARMONIC5
X-RAY DIFFRACTIONt_it2457HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion312SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2887SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2457HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3370HARMONIC21.06
X-RAY DIFFRACTIONt_omega_torsion3.01
X-RAY DIFFRACTIONt_other_torsion18.17
LS refinement shellResolution: 2.33→2.34 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2341 24 3.6 %
Rwork0.2324 642 -
all0.2325 666 -
obs--100 %

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