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- PDB-4mfb: Crystal Structure of HIV-1 Reverse Transcriptase in Complex with ... -

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Basic information

Entry
Database: PDB / ID: 4mfb
TitleCrystal Structure of HIV-1 Reverse Transcriptase in Complex with 8-(2-(2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)phenoxy)indolizine-2-carbonitrile (JLJ555), a non-nucleoside inhibitor
Components
  • HIV-1 reverse transcriptase, p51 subunit
  • HIV-1 reverse transcriptase, p66 subunit
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Polymerase / Transferase / Hydrolase / RnaseH / Rnase / HYDROLASE-HYDROLASE INHIBITOR complex
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 / RNA stem-loop binding / RNA-directed DNA polymerase activity / RNA-DNA hybrid ribonuclease activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / host cell / viral nucleocapsid / DNA recombination / DNA-directed DNA polymerase / aspartic-type endopeptidase activity / Hydrolases; Acting on ester bonds / DNA-directed DNA polymerase activity / symbiont-mediated suppression of host gene expression / viral translational frameshifting / lipid binding / symbiont entry into host cell / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / proteolysis / DNA binding / zinc ion binding / membrane
Similarity search - Function
HIV Type 1 Reverse Transcriptase, subunit A, domain 1 / HIV Type 1 Reverse Transcriptase; Chain A, domain 1 / Reverse transcriptase/Diguanylate cyclase domain / 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. ...HIV Type 1 Reverse Transcriptase, subunit A, domain 1 / HIV Type 1 Reverse Transcriptase; Chain A, domain 1 / Reverse transcriptase/Diguanylate cyclase domain / 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 / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Reverse transcriptase domain / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase (RT) catalytic domain profile. / 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 / Alpha-Beta Plaits / Roll / DNA/RNA polymerase superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-29T / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.88 Å
AuthorsFrey, K.M. / Anderson, K.S.
CitationJournal: J.Am.Chem.Soc. / Year: 2013
Title: Picomolar Inhibitors of HIV Reverse Transcriptase Featuring Bicyclic Replacement of a Cyanovinylphenyl Group.
Authors: Lee, W.G. / Gallardo-Macias, R. / Frey, K.M. / Spasov, K.A. / Bollini, M. / Anderson, K.S. / Jorgensen, W.L.
History
DepositionAug 27, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 6, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2013Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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: HIV-1 reverse transcriptase, p66 subunit
B: HIV-1 reverse transcriptase, p51 subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,4173
Polymers114,0292
Non-polymers3881
Water30617
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4730 Å2
ΔGint-21 kcal/mol
Surface area47930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)223.946, 69.404, 104.874
Angle α, β, γ (deg.)90.000, 105.870, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein HIV-1 reverse transcriptase, p66 subunit


Mass: 63989.238 Da / Num. of mol.: 1
Fragment: HIV-1 reverse transcriptase, p66 subunit (chain A)
Mutation: C280S, K172A, K173A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 / Strain: Bh10 Isolate / Gene: gag-pol / Plasmid: pCDF-2 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P03366, RNA-directed DNA polymerase
#2: Protein HIV-1 reverse transcriptase, p51 subunit


Mass: 50039.488 Da / Num. of mol.: 1
Fragment: HIV-1 reverse transcriptase, p51 subunit (chain B)
Mutation: C280S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 / Strain: Bh10 Isolate / Gene: gag-pol / Plasmid: pCDF-2 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P03366, RNA-directed DNA polymerase
#3: Chemical ChemComp-29T / 8-{2-[2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenoxy}indolizine-2-carbonitrile


Mass: 388.376 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H16N4O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / 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: 3.44 Å3/Da / Density % sol: 64.22 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 12.5% (w/v) PEG 8,000, 100 mM ammonium sulfate, 15 mM magnesium sulfate, 5 mM spermine, and 50 mM MES pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 3, 2012 / Details: Monochromator
RadiationMonochromator: Cryogenically cooled double crystal monochrometer with horizontal focusing sagittal bend second mono crystal with 4:1 magnification ratio and vertically focusing mirror.
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 2.88→50 Å / Num. all: 35107 / Num. obs: 35128 / % possible obs: 99 % / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Biso Wilson estimate: 80.34 Å2 / Rsym value: 0.067 / Χ2: 1.797 / Net I/σ(I): 28.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.88-2.933.40.47915850.883191.2
2.93-2.983.60.40417400.926198.6
2.98-3.043.70.37917470.968199.2
3.04-3.13.80.34217531.096199.7
3.1-3.173.80.26617571.073199.7
3.17-3.243.80.21817541.268199.7
3.24-3.323.80.19217601.383199.8
3.32-3.413.80.16917521.467199.8
3.41-3.513.80.16717502.285199.9
3.51-3.633.80.12417841.777199.9
3.63-3.763.80.10817612.1981100
3.76-3.913.80.09717742.5821100
3.91-4.093.80.0817772.315199.9
4.09-4.33.80.06917622.373199.9
4.3-4.573.70.06317712.508199.8
4.57-4.923.80.05817852.415199.7
4.92-5.423.70.05617842.4831100
5.42-6.23.70.05517862.426199.9
6.2-7.813.60.0418051.791199.9
7.81-503.50.02817411.404193.4

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHENIX1.8.2_1309refinement
PDB_EXTRACT3.11data extraction
CBASSdata collection
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4H4M

4h4m


Resolution: 2.88→36.603 Å / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7247 / SU ML: 0.45 / Cross valid method: Rfree Flag / σ(F): 1.36 / Phase error: 33.28 / Stereochemistry target values: Maximum Likelihood (ML)
RfactorNum. reflection% reflectionSelection details
Rfree0.2694 1998 5.69 %Random
Rwork0.2368 ---
all0.2387 35107 --
obs0.2368 35107 99.09 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 313.9 Å2 / Biso mean: 76.2151 Å2 / Biso min: 20.36 Å2
Refinement stepCycle: LAST / Resolution: 2.88→36.603 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7831 0 29 17 7877
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0038077
X-RAY DIFFRACTIONf_angle_d0.7710976
X-RAY DIFFRACTIONf_chiral_restr0.0591184
X-RAY DIFFRACTIONf_plane_restr0.0031381
X-RAY DIFFRACTIONf_dihedral_angle_d12.9693062
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection allNum. reflection obs% reflection obs (%)
2.88-2.95130.35121340.327422152349221595
2.9513-3.03110.37491420.327523532495235399
3.0311-3.12020.391420.3119234624882346100
3.1202-3.22090.40481430.3046236825112368100
3.2209-3.33590.36731420.2877237525172375100
3.3359-3.46940.32731450.2824238425292384100
3.4694-3.62710.30271410.2763235124922351100
3.6271-3.81820.29461440.2542237625202376100
3.8182-4.05710.26311440.242239125352391100
4.0571-4.36990.24411440.2081239325372393100
4.3699-4.80880.22941430.2035235925022359100
4.8088-5.50260.25471450.2125239525402395100
5.5026-6.9250.27311470.2392243725842437100
6.925-36.60640.20891420.201823662508236695

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