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- PDB-5c42: Crystal Structure of HIV-1 Reverse Transcriptase (K101P) Variant ... -

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Basic information

Entry
Database: PDB / ID: 5c42
TitleCrystal Structure of HIV-1 Reverse Transcriptase (K101P) Variant 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
KeywordsTRANSFERASE / HYDROLASE/INHIBITOR / HIV / reverse transcriptase / polymerase / non-nucleoside inhibitor / resistance / 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 group M subtype B
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 3.5 Å
AuthorsFrey, K.M. / Gray, W.T. / Anderson, K.S.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI44616 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM49551 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI104334 United States
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance.
Authors: Gray, W.T. / Frey, K.M. / Laskey, S.B. / Mislak, A.C. / Spasov, K.A. / Lee, W.G. / Bollini, M. / Siliciano, R.F. / Jorgensen, W.L. / Anderson, K.S.
History
DepositionJun 17, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 11, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 13, 2017Group: Author supporting evidence / Derived calculations / Category: pdbx_audit_support / pdbx_struct_oper_list
Item: _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software / Item: _software.classification
Revision 1.3Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)114,3853
Polymers113,9972
Non-polymers3881
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4790 Å2
ΔGint-23 kcal/mol
Surface area48110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)224.198, 69.008, 104.283
Angle α, β, γ (deg.)90.00, 106.49, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein HIV-1 Reverse Transcriptase, p66 subunit / Pr160Gag-Pol


Mass: 63957.176 Da / Num. of mol.: 1 / Fragment: UNP residues 600-1154 / Mutation: K101P, K172A, K173A, C280S
Source method: isolated from a genetically manipulated source
Details: Lentivirus
Source: (gene. exp.) Human immunodeficiency virus type 1 group M subtype B (isolate BH10)
Strain: isolate BH10 / Gene: gag-pol / Plasmid: pCDF-2 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3)
References: UniProt: P03366, HIV-1 retropepsin, RNA-directed DNA polymerase, DNA-directed DNA polymerase, retroviral ribonuclease H, exoribonuclease H
#2: Protein HIV-1 Reverse Transcriptase, p51 subunit / Pr160Gag-Pol


Mass: 50039.488 Da / Num. of mol.: 1 / Fragment: UNP residues 600-1027 / Mutation: C280S
Source method: isolated from a genetically manipulated source
Details: Lentivirus
Source: (gene. exp.) Human immunodeficiency virus type 1 group M subtype B (isolate BH10)
Strain: isolate BH10 / Gene: gag-pol / Plasmid: pCDF-2 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3)
References: UniProt: P03366, HIV-1 retropepsin, RNA-directed DNA polymerase, DNA-directed DNA polymerase, retroviral ribonuclease H, exoribonuclease H
#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

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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: 3.39 Å3/Da / Density % sol: 63.75 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: co-crystallization; 15% PEG 8000 (50% (w/v)), in pH 7.0 solution (0.125 M HEPES, 0.0125 M spermine-HCl, 0.04 M magnesium sulfate, 0.04 M ammonium sulfate)

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Data collection

DiffractionMean temperature: 80 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 27, 2014
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 3.5→50 Å / Num. obs: 23862 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Rsym value: 0.083 / Net I/σ(I): 24.1
Reflection shellResolution: 3.5→3.56 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.603 / Mean I/σ(I) obs: 1.94 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-3000phasing
HKL-3000data scaling
PHENIXDifference Fourier Methodsphasing
RefinementResolution: 3.5→38.223 Å / SU ML: 0.59 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 33.94 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2823 1633 8.39 %Random
Rwork0.2442 ---
obs0.2474 19469 99.33 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.5→38.223 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7894 0 29 0 7923
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0038145
X-RAY DIFFRACTIONf_angle_d0.87611079
X-RAY DIFFRACTIONf_dihedral_angle_d13.7013075
X-RAY DIFFRACTIONf_chiral_restr0.0311198
X-RAY DIFFRACTIONf_plane_restr0.0041397
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.5-3.6030.40421360.34571464X-RAY DIFFRACTION98
3.603-3.71920.3881300.31721441X-RAY DIFFRACTION99
3.7192-3.8520.33911370.29961491X-RAY DIFFRACTION100
3.852-4.0060.33781340.2851468X-RAY DIFFRACTION100
4.006-4.18810.28611370.25871496X-RAY DIFFRACTION100
4.1881-4.40860.31911340.25281461X-RAY DIFFRACTION100
4.4086-4.68440.33641380.23141494X-RAY DIFFRACTION100
4.6844-5.04530.27981350.22141486X-RAY DIFFRACTION100
5.0453-5.55170.28781380.23261495X-RAY DIFFRACTION100
5.5517-6.35190.31341380.25421508X-RAY DIFFRACTION100
6.3519-7.99060.29951380.25311514X-RAY DIFFRACTION100
7.9906-38.22520.21671380.21991518X-RAY DIFFRACTION97

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