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- PDB-4m8y: GS-8374, a Novel Phosphonate-Containing Inhibitor of HIV-1 Protea... -

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Basic information

Entry
Database: PDB / ID: 4m8y
TitleGS-8374, a Novel Phosphonate-Containing Inhibitor of HIV-1 Protease, Effectively Inhibits HIV PR Mutants with Amino Acid Insertions
ComponentsProtease
KeywordsHydrolase/Hydrolase Inhibitor / HIV-1 protease / aspartic protease / amino acid insertion / Hydrolase-Hydrolase Inhibitor complex
Function / homology
Function and homology information


viral genome integration into host DNA / establishment of integrated proviral latency / RNA stem-loop binding / RNA-directed DNA polymerase activity / endonuclease activity / aspartic-type endopeptidase activity / proteolysis / DNA binding / zinc ion binding
Similarity search - Function
Reverse transcriptase thumb / Reverse transcriptase thumb domain / Retropepsin-like catalytic 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. ...Reverse transcriptase thumb / Reverse transcriptase thumb domain / Retropepsin-like catalytic 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. / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Reverse transcriptase/Diguanylate cyclase domain / DNA/RNA polymerase superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-KGQ / Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.22 Å
AuthorsGrantz saskova, K. / Brynda, J. / Rezacova, P. / Kozisek, M. / Konvalinka, J.
CitationJournal: J.Virol. / Year: 2014
Title: GS-8374, a prototype phosphonate-containing inhibitor of HIV-1 protease, effectively inhibits protease mutants with amino acid insertions.
Authors: Grantz Saskova, K. / Kozisek, M. / Stray, K. / de Jong, D. / Rezaova, P. / Brynda, J. / van Maarseveen, N.M. / Nijhuis, M. / Cihlar, T. / Konvalinka, J.
History
DepositionAug 14, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 7, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 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

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Assembly

Deposited unit
A: Protease
B: Protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,2834
Polymers21,8262
Non-polymers1,4582
Water1,42379
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)61.905, 61.905, 83.178
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61

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Components

#1: Protein Protease


Mass: 10912.771 Da / Num. of mol.: 2
Mutation: L10F, I13V, G16A, K20M, D37S, I46V, I54M, A71V, GLU INSERSION AFTER 33
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: pol / Plasmid: pET24a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)RIL / References: UniProt: Q90JJ9, HIV-1 retropepsin
#2: Chemical ChemComp-KGQ / DIETHYL ({4-[(2S,3R)-2-({[(3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YLOXY]CARBONYL}AMINO)-3-HYDROXY-4-{ISOBUTYL[(4-METHOXYPHENYL)SULFONYL]AMINO}BUTYL]PHENOXY}METHYL)PHOSPHONATE


Mass: 728.787 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H49N2O12PS
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 79 / 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: 2.11 Å3/Da / Density % sol: 41.65 %
Crystal growTemperature: 292.15 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 0.5 ammonium sulphate and 0.1 M MES pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 292.15K

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Data collection

DiffractionMean temperature: 120 K
Diffraction sourceSource: ROTATING ANODE / Type: OTHER / Wavelength: 1.54 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Jan 1, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionHighest resolution: 2.22 Å / Num. all: 8906 / Num. obs: 8455

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Processing

Software
NameVersionClassification
MAR345dtbdata collection
REFMAC5.5.0109refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2RKG

2rkg


Resolution: 2.22→32.86 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.889 / SU B: 8.44 / SU ML: 0.208 / Cross valid method: THROUGHOUT / ESU R: 0.466 / ESU R Free: 0.273 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.26783 422 4.8 %RANDOM
Rwork0.19788 ---
obs0.20107 8453 99.37 %-
all-8906 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 35.014 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3----0.01 Å2
Refinement stepCycle: LAST / Resolution: 2.22→32.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1524 0 98 79 1701
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.021676
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.5082.0412287
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2415202
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.20524.91559
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.71515271
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.579157
X-RAY DIFFRACTIONr_chiral_restr0.0880.2274
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211193
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.223→2.281 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.275 26 -
Rwork0.212 549 -
obs--91.56 %

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