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- PDB-5tuq: Crystal Structure of a 6-Cyclohexylmethyl-3-hydroxypyrimidine-2,4... -

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Basic information

Entry
Database: PDB / ID: 5tuq
TitleCrystal Structure of a 6-Cyclohexylmethyl-3-hydroxypyrimidine-2,4-dione Inhibitor in Complex with HIV Reverse Transcriptase
Components(HIV-1 REVERSE TRANSCRIPTASE) x 2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / HIV-1 / REVERSE TRANSCRIPTASE / INHIBITOR / TRANSFERASE-TRANSFERASE 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 / DNA integration / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency / RNA stem-loop binding ...HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / DNA integration / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency / RNA stem-loop binding / viral penetration into host nucleus / host multivesicular body / 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 / Hydrolases; Acting on ester bonds / aspartic-type endopeptidase activity / 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 / RNase H type-1 domain profile. / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Ribonuclease H domain / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Retrovirus capsid, C-terminal / Reverse transcriptase domain / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase (RT) catalytic domain profile. / 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-J63 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus type 1 group M subtype B
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.705 Å
AuthorsKirby, K.A. / Sarafianos, S.G.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI100890 United States
CitationJournal: Eur J Med Chem / Year: 2017
Title: 6-Cyclohexylmethyl-3-hydroxypyrimidine-2,4-dione as an inhibitor scaffold of HIV reverase transcriptase: Impacts of the 3-OH on inhibiting RNase H and polymerase.
Authors: Tang, J. / Kirby, K.A. / Huber, A.D. / Casey, M.C. / Ji, J. / Wilson, D.J. / Sarafianos, S.G. / Wang, Z.
History
DepositionNov 7, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 28, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 4, 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: HIV-1 REVERSE TRANSCRIPTASE
B: HIV-1 REVERSE TRANSCRIPTASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,6134
Polymers114,2022
Non-polymers4112
Water2,198122
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5290 Å2
ΔGint-38 kcal/mol
Surface area45880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)161.901, 72.355, 107.334
Angle α, β, γ (deg.)90.000, 99.870, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein HIV-1 REVERSE TRANSCRIPTASE / Pr160Gag-Pol


Mass: 64105.441 Da / Num. of mol.: 1 / Fragment: p66 domain residues 600-1154 / Mutation: C280S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 group M subtype B (isolate BH10)
Strain: isolate BH10 / Gene: gag-pol / Plasmid: pET35a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) RIL
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 / Pr160Gag-Pol


Mass: 50096.539 Da / Num. of mol.: 1 / Fragment: p51 domain residues 600-1027 / Mutation: C280S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 group M subtype B (isolate BH10)
Strain: isolate BH10 / Gene: gag-pol / Plasmid: pET35a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) RIL
References: UniProt: P03366, HIV-1 retropepsin, RNA-directed DNA polymerase, DNA-directed DNA polymerase, retroviral ribonuclease H, exoribonuclease H
#3: Chemical ChemComp-J63 / 1-[(benzyloxy)methyl]-6-(cyclohexylmethyl)-3-hydroxy-5-(propan-2-yl)pyrimidine-2,4(1H,3H)-dione


Mass: 386.485 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H30N2O4
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 122 / 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: 2.71 Å3/Da / Density % sol: 54.64 % / Mosaicity: 0.18 °
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 6.1
Details: PEG 3350, SODIUM POTASSIUM PHOSPHATE, ETHYLENE GLYCOL, MES

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.03 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Apr 10, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03 Å / Relative weight: 1
ReflectionResolution: 2.7→48.02 Å / Num. obs: 33593 / % possible obs: 99.7 % / Redundancy: 7.6 % / Biso Wilson estimate: 77.07 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.086 / Rpim(I) all: 0.033 / Rrim(I) all: 0.092 / Net I/σ(I): 14.7 / Num. measured all: 254208 / Scaling rejects: 0
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique allCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.7-2.847.61.1823291143290.7640.4581.2681.897.8
8.97-48.026.80.03865699690.9980.0160.04142.599.3

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation8.1 Å48.02 Å
Translation8.1 Å48.02 Å

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575)refinement
Aimless0.5.25data scaling
PHASER2.6.1phasing
PDB_EXTRACT3.2data extraction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4G1Q

4g1q


Resolution: 2.705→48.022 Å / SU ML: 0.41 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 32.1 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2647 1680 5 %
Rwork0.2125 31903 -
obs0.2152 33583 99.68 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 182.46 Å2 / Biso mean: 97.21 Å2 / Biso min: 46.76 Å2
Refinement stepCycle: final / Resolution: 2.705→48.022 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7870 0 29 122 8021
Biso mean--98.36 85.78 -
Num. residues----960
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0038113
X-RAY DIFFRACTIONf_angle_d0.66911021
X-RAY DIFFRACTIONf_chiral_restr0.0451192
X-RAY DIFFRACTIONf_plane_restr0.0051384
X-RAY DIFFRACTIONf_dihedral_angle_d16.3224890
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.7046-2.78420.37581450.31122559270496
2.7842-2.87410.34231430.291326362779100
2.8741-2.97680.28281330.263226202753100
2.9768-3.09590.36481110.248826742785100
3.0959-3.23680.33461280.236126702798100
3.2368-3.40740.28551430.232526642807100
3.4074-3.62080.31041300.224926462776100
3.6208-3.90030.26181570.208326582815100
3.9003-4.29260.26611550.197726482803100
4.2926-4.91320.23391440.1926862830100
4.9132-6.1880.24941470.215626822829100
6.188-48.02960.23771440.193427602904100
Refinement TLS params.Method: refined / Origin x: 41.2839 Å / Origin y: -0.9885 Å / Origin z: 28.5384 Å
111213212223313233
T0.5272 Å2-0.0136 Å20.086 Å2-0.4902 Å2-0.0424 Å2--0.5215 Å2
L1.6893 °2-0.7788 °21.6816 °2-1.0843 °2-0.8116 °2--2.5225 °2
S0.0724 Å °0.0085 Å °-0.1659 Å °0.3305 Å °0.0275 Å °-0.0027 Å °-0.0166 Å °0.0473 Å °-0.0974 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA0 - 561
2X-RAY DIFFRACTION1allB5 - 428
3X-RAY DIFFRACTION1allS2 - 139

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