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- PDB-5j1e: Crystal Structure of a Hydroxypyridone Carboxylic Acid Active-Sit... -

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Basic information

Entry
Database: PDB / ID: 5j1e
TitleCrystal Structure of a Hydroxypyridone Carboxylic Acid Active-Site RNase H Inhibitor in Complex with HIV Reverse Transcriptase
Components
  • HIV-1 REVERSE TRANSCRIPTASE P51 DOMAIN
  • HIV-1 REVERSE TRANSCRIPTASE P66 DOMAIN
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


HIV-1 retropepsin / : / retroviral ribonuclease H / exoribonuclease H / : / exoribonuclease H activity / host multivesicular body / DNA integration / RNA-directed DNA polymerase / viral genome integration into host DNA ...HIV-1 retropepsin / : / retroviral ribonuclease H / exoribonuclease H / : / exoribonuclease H activity / host multivesicular body / DNA integration / RNA-directed DNA polymerase / viral genome integration into host DNA / viral penetration into host nucleus / establishment of integrated proviral latency / RNA-directed DNA polymerase activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / RNA-DNA hybrid ribonuclease activity / viral nucleocapsid / DNA recombination / Hydrolases; Acting on ester bonds / DNA-directed DNA polymerase / aspartic-type endopeptidase activity / DNA-directed DNA polymerase activity / symbiont entry into host cell / symbiont-mediated suppression of host gene expression / lipid binding / host cell nucleus / structural molecule activity / host cell plasma membrane / virion membrane / proteolysis / DNA binding / RNA 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. / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Retropepsin-like catalytic domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Ribonuclease H domain / RNase H type-1 domain profile. / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase domain / 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 / Ribonuclease H superfamily / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain 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-6FT / 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: 2.9 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: J.Med.Chem. / Year: 2016
Title: Design, Synthesis, and Biological Evaluations of Hydroxypyridonecarboxylic Acids as Inhibitors of HIV Reverse Transcriptase Associated RNase H.
Authors: Kankanala, J. / Kirby, K.A. / Liu, F. / Miller, L. / Nagy, E. / Wilson, D.J. / Parniak, M.A. / Sarafianos, S.G. / Wang, Z.
History
DepositionMar 29, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 15, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 29, 2016Group: Database references
Revision 1.2Sep 20, 2017Group: Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_audit_support / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Sep 27, 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 P66 DOMAIN
B: HIV-1 REVERSE TRANSCRIPTASE P51 DOMAIN
C: HIV-1 REVERSE TRANSCRIPTASE P66 DOMAIN
D: HIV-1 REVERSE TRANSCRIPTASE P51 DOMAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)228,8778
Polymers228,4044
Non-polymers4734
Water362
1
A: HIV-1 REVERSE TRANSCRIPTASE P66 DOMAIN
B: HIV-1 REVERSE TRANSCRIPTASE P51 DOMAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,2263
Polymers114,2022
Non-polymers241
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5760 Å2
ΔGint-41 kcal/mol
Surface area45070 Å2
MethodPISA
2
C: HIV-1 REVERSE TRANSCRIPTASE P66 DOMAIN
D: HIV-1 REVERSE TRANSCRIPTASE P51 DOMAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,6515
Polymers114,2022
Non-polymers4493
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5480 Å2
ΔGint-39 kcal/mol
Surface area45620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.070, 89.310, 108.220
Angle α, β, γ (deg.)105.470, 92.690, 110.800
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain D and (resseq 7 or (resid 8 and (name...
21(chain B and (resseq 7 or (resid 8 and (name...
12(chain A and (resseq 4:10 or resseq 12:21 or resseq...
22(chain C and (resseq 4:10 or resseq 12:21 or resseq...

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain D and (resseq 7 or (resid 8 and (name...D7
121(chain D and (resseq 7 or (resid 8 and (name...D8
131(chain D and (resseq 7 or (resid 8 and (name...D7 - 427
141(chain D and (resseq 7 or (resid 8 and (name...D7 - 427
151(chain D and (resseq 7 or (resid 8 and (name...D7 - 427
161(chain D and (resseq 7 or (resid 8 and (name...D7 - 427
171(chain D and (resseq 7 or (resid 8 and (name...D7 - 427
211(chain B and (resseq 7 or (resid 8 and (name...B7
221(chain B and (resseq 7 or (resid 8 and (name...B8
231(chain B and (resseq 7 or (resid 8 and (name...B0 - 427
241(chain B and (resseq 7 or (resid 8 and (name...B0 - 427
251(chain B and (resseq 7 or (resid 8 and (name...B0 - 427
261(chain B and (resseq 7 or (resid 8 and (name...B0 - 427
271(chain B and (resseq 7 or (resid 8 and (name...B0 - 427
112(chain A and (resseq 4:10 or resseq 12:21 or resseq...A4 - 10
122(chain A and (resseq 4:10 or resseq 12:21 or resseq...A12 - 21
132(chain A and (resseq 4:10 or resseq 12:21 or resseq...A23 - 27
142(chain A and (resseq 4:10 or resseq 12:21 or resseq...A29 - 63
152(chain A and (resseq 4:10 or resseq 12:21 or resseq...A71
162(chain A and (resseq 4:10 or resseq 12:21 or resseq...A73 - 75
172(chain A and (resseq 4:10 or resseq 12:21 or resseq...A76
182(chain A and (resseq 4:10 or resseq 12:21 or resseq...A4 - 560
192(chain A and (resseq 4:10 or resseq 12:21 or resseq...A4 - 560
1102(chain A and (resseq 4:10 or resseq 12:21 or resseq...A4 - 560
1112(chain A and (resseq 4:10 or resseq 12:21 or resseq...A4 - 560
1122(chain A and (resseq 4:10 or resseq 12:21 or resseq...A4 - 560
1132(chain A and (resseq 4:10 or resseq 12:21 or resseq...A4 - 560
212(chain C and (resseq 4:10 or resseq 12:21 or resseq...C4 - 10
222(chain C and (resseq 4:10 or resseq 12:21 or resseq...C12 - 21
232(chain C and (resseq 4:10 or resseq 12:21 or resseq...C23 - 27
242(chain C and (resseq 4:10 or resseq 12:21 or resseq...C29 - 63
252(chain C and (resseq 4:10 or resseq 12:21 or resseq...C71
262(chain C and (resseq 4:10 or resseq 12:21 or resseq...C73 - 75
272(chain C and (resseq 4:10 or resseq 12:21 or resseq...C76
282(chain C and (resseq 4:10 or resseq 12:21 or resseq...C3 - 562
292(chain C and (resseq 4:10 or resseq 12:21 or resseq...C3 - 562
2102(chain C and (resseq 4:10 or resseq 12:21 or resseq...C3 - 562
2112(chain C and (resseq 4:10 or resseq 12:21 or resseq...C3 - 562
2122(chain C and (resseq 4:10 or resseq 12:21 or resseq...C3 - 562
2132(chain C and (resseq 4:10 or resseq 12:21 or resseq...C3 - 562

NCS ensembles :
ID
1
2

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Components

#1: Protein HIV-1 REVERSE TRANSCRIPTASE P66 DOMAIN / Pr160Gag-Pol


Mass: 64105.441 Da / Num. of mol.: 2 / 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, RNA-directed DNA polymerase, DNA-directed DNA polymerase, ribonuclease H
#2: Protein HIV-1 REVERSE TRANSCRIPTASE P51 DOMAIN / Pr160Gag-Pol


Mass: 50096.539 Da / Num. of mol.: 2 / 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, RNA-directed DNA polymerase, DNA-directed DNA polymerase, ribonuclease H
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-6FT / 5-hydroxy-4-oxo-1-[(4'-sulfamoyl[1,1'-biphenyl]-4-yl)methyl]-1,4-dihydropyridine-3-carboxylic acid


Mass: 400.405 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H16N2O6S
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 2 / 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: 2.6 Å3/Da / Density % sol: 52.7 %
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: ALS / Beamline: 4.2.2 / Wavelength: 0.976 Å
DetectorType: RDI CMOS_8M / Detector: CMOS / Date: Jan 24, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.9→63.77 Å / Num. obs: 49891 / % possible obs: 97.8 % / Redundancy: 7.4 % / Biso Wilson estimate: 61.76 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.086 / Rpim(I) all: 0.034 / Rrim(I) all: 0.093 / Net I/σ(I): 17.9 / Num. measured all: 367887
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique allCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.9-37.40.7243399845940.870.2850.7793.197.5
11.6-63.776.90.03254327850.9990.0140.03551.898.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155)refinement
XSCALEdata scaling
PHASERphasing
PDB_EXTRACT3.2data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1DLO

1dlo


Resolution: 2.9→63.765 Å / SU ML: 0.47 / Cross valid method: FREE R-VALUE / σ(F): 1.98 / Phase error: 34.24 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2945 2493 5 %
Rwork0.254 47375 -
obs0.256 49868 97.81 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 218.86 Å2 / Biso mean: 74.6396 Å2 / Biso min: 34.04 Å2
Refinement stepCycle: final / Resolution: 2.9→63.765 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15451 0 31 2 15484
Biso mean--82.82 39.38 -
Num. residues----1887
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00415908
X-RAY DIFFRACTIONf_angle_d0.56721593
X-RAY DIFFRACTIONf_chiral_restr0.0432341
X-RAY DIFFRACTIONf_plane_restr0.0042713
X-RAY DIFFRACTIONf_dihedral_angle_d13.9999566
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11D3322X-RAY DIFFRACTION9.225TORSIONAL
12B3322X-RAY DIFFRACTION9.225TORSIONAL
21A4548X-RAY DIFFRACTION9.225TORSIONAL
22C4548X-RAY DIFFRACTION9.225TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 18

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.9-2.95580.39811280.34882577270598
2.9558-3.01610.36691260.32292652277897
3.0161-3.08170.36481400.33582630277097
3.0817-3.15340.37591480.3112631277997
3.1534-3.23220.381120.31392602271497
3.2322-3.31960.33491370.29832617275496
3.3196-3.41730.35481320.29242603273597
3.4173-3.52760.35811450.27792627277298
3.5276-3.65370.28531310.26572642277397
3.6537-3.79990.35831440.26032584272897
3.7999-3.97280.28861360.24072574271095
3.9728-4.18230.28811390.23362654279399
4.1823-4.44420.2531490.22582651280099
4.4442-4.78730.26591550.21772662281799
4.7873-5.26880.26121430.22312684282799
5.2688-6.03070.31111140.25152679279399
6.0307-7.59610.27421560.25442664282099
7.5961-63.78080.23881580.22452642280099
Refinement TLS params.Method: refined / Origin x: -29.0538 Å / Origin y: 61.2343 Å / Origin z: -43.8698 Å
111213212223313233
T0.3945 Å2-0.0176 Å20.0017 Å2-0.4293 Å2-0.0512 Å2--0.4982 Å2
L0.2407 °2-0.2455 °20.3073 °2-0.2519 °2-0.2183 °2--0.456 °2
S-0.0034 Å °0.0366 Å °0.008 Å °-0.03 Å °-0.0197 Å °-0.0428 Å °-0.0188 Å °-0.0319 Å °-0 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA4 - 560
2X-RAY DIFFRACTION1allB0 - 427
3X-RAY DIFFRACTION1allC3 - 562
4X-RAY DIFFRACTION1allD7 - 427
5X-RAY DIFFRACTION1allE1 - 2

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