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- PDB-4m8x: GS-8374, a Novel Phosphonate-Containing Inhibitor of HIV-1 Protea... -

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Basic information

Entry
Database: PDB / ID: 4m8x
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 protease / aspartic protease / GS8374 / 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 / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 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_ncs_dom_lim / 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_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_alt_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_alt_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id / _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: Protease
B: Protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,0254
Polymers21,5672
Non-polymers1,4582
Water1,33374
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6220 Å2
ΔGint-22 kcal/mol
Surface area9100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.756, 61.756, 83.352
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22B

NCS domain segments:

Component-ID: 1

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDRefine codeAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-IDBeg label alt-IDEnd label alt-ID
11PROPROPHEPHE2AA1 - 991 - 99
21PROPROPHEPHE2BB1 - 991 - 99
12KGQKGQKGQKGQ4BC101AA
22KGQKGQKGQKGQ4BD102BB

NCS ensembles :
ID
1
2

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Components

#1: Protein Protease


Mass: 10783.658 Da / Num. of mol.: 2 / Mutation: L10F, I13V, G16A, K20M, D37S, I46V, I54M, A71V
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.: 74 / 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: 2.13 Å3/Da / Density % sol: 42.18 %
Crystal growTemperature: 292.15 K / Method: vapor diffusion, hanging drop
Details: 0.5 M ammonium sulphate and 0.1 M sodium acetate pH 5.25-5.5, VAPOR DIFFUSION, HANGING DROP, temperature 292.15K
PH range: 5.25-5.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-BM / Wavelength: 0.9793 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jul 1, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionHighest resolution: 2.05 Å / Num. all: 11333 / Num. obs: 10764

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Processing

Software
NameVersionClassification
HKL-2000data collection
REFMAC5.5.0109refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2RKF

2rkf


Resolution: 2.05→53.45 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.938 / SU B: 16.431 / SU ML: 0.208 / Cross valid method: THROUGHOUT / ESU R: 0.278 / ESU R Free: 0.222 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26576 538 4.8 %RANDOM
Rwork0.20069 ---
all0.20339 10832 --
obs0.20339 10764 99.37 %-
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: 55.426 Å2
Baniso -1Baniso -2Baniso -3
1-0.13 Å20.07 Å20 Å2
2--0.13 Å20 Å2
3----0.2 Å2
Refinement stepCycle: LAST / Resolution: 2.05→53.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 98 74 1684
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0221685
X-RAY DIFFRACTIONr_bond_other_d0.0060.021131
X-RAY DIFFRACTIONr_angle_refined_deg1.6952.0342301
X-RAY DIFFRACTIONr_angle_other_deg0.9233.0082690
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2355202
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.34524.42661
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.20615274
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.789158
X-RAY DIFFRACTIONr_chiral_restr0.0980.2275
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211769
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02299
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_it1.0561.5989
X-RAY DIFFRACTIONr_mcbond_other0.1481.5415
X-RAY DIFFRACTIONr_mcangle_it1.9721616
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.1413696
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.6424.5682
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
Refine LS restraints NCS

Auth asym-ID: A / Refine-ID: X-RAY DIFFRACTION

Ens-IDDom-IDNumberTypeRms dev position (Å)Weight position
11576tight positional0.10.05
11713medium positional0.470.5
2282medium positional0.110.5
11576tight thermal0.260.5
11713medium thermal0.282
2282medium thermal0.382
LS refinement shellResolution: 2.05→2.103 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.377 38 -
Rwork0.319 758 -
obs-796 94.65 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.9361-0.2191-0.20053.1328-0.87375.62890.0520.08020.10370.0171-0.0998-0.2382-0.10.28580.04770.2872-0.05-0.01720.31840.03660.07661.11756.352.724
20.47520.8688-0.95454.4797-1.74832.20670.02170.05720.1147-0.02480.13380.07350.0261-0.2146-0.15550.3053-0.0075-0.02610.3610.08510.0781-6.50662.882-5.093
37.48174.7642-5.55924.3864-2.92834.543-0.5811.19760.8854-0.1710.82060.64120.3778-0.8155-0.23970.2307-0.1702-0.16880.51630.2250.1333-17.54158.952-10.118
40.75180.6848-0.86912.5344-1.52766.0523-0.0189-0.172-0.0355-0.0357-0.0838-0.17510.15170.32760.10270.30470.03360.00090.30650.04090.07681.12850.655.473
50.6063-1.1230.69135.2651-1.72472.65640.0411-0.0408-0.12940.02070.13640.0383-0.0299-0.2716-0.17750.3103-0.00690.01480.34060.08010.0743-6.49944.06313.231
68.9188-5.15157.50645.9165-5.230110.5154-0.3684-1.2728-1.19980.21610.88741.0302-0.3614-0.9116-0.5190.22050.12820.19030.50.23560.1516-17.55147.99618.212
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 9
2X-RAY DIFFRACTION1A86 - 99
3X-RAY DIFFRACTION2A10 - 32
4X-RAY DIFFRACTION2A63 - 85
5X-RAY DIFFRACTION3A33 - 62
6X-RAY DIFFRACTION4B1 - 9
7X-RAY DIFFRACTION4B86 - 99
8X-RAY DIFFRACTION5B10 - 32
9X-RAY DIFFRACTION5B63 - 85
10X-RAY DIFFRACTION6B33 - 62

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