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- PDB-1t7i: The structural and thermodynamic basis for the binding of TMC114,... -

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Basic information

Entry
Database: PDB / ID: 1t7i
TitleThe structural and thermodynamic basis for the binding of TMC114, a next-generation HIV-1 protease inhibitor.
ComponentsPol Polyprotein
KeywordsHYDROLASE / HIV-1 PROTEASE / DRUG RESITANCE / THERMODYNAMICS / SUBSTRATE ENVELOPE
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 / 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
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 ...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 / Cathepsin D, subunit A; domain 1 / Acid Proteases / Retrovirus capsid, N-terminal / zinc finger / Zinc knuckle / Zinc finger, CCHC-type superfamily / Zinc finger, CCHC-type / Zinc finger CCHC-type profile. / 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 / DNA/RNA polymerase superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-017 / ACETATE ION / PHOSPHATE ION / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.35 Å
AuthorsKing, N.M. / Prabu-Jeyabalan, M. / Nalivaika, E.A. / Wigerinck, P.B.T.P. / De Bethune, M.-P. / Schiffer, C.A.
CitationJournal: J.Med.Chem. / Year: 2005
Title: Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor
Authors: Surleraux, D.L.N.G. / Tahri, A. / Verschueren, W.G. / Pille, G.M.E. / de Kock, H.A. / Jonckers, T.H.M. / Peeters, A. / De Meyer, S. / Azijn, H. / Pauwels, R. / de Bethune, M.-P. / King, N.M. ...Authors: Surleraux, D.L.N.G. / Tahri, A. / Verschueren, W.G. / Pille, G.M.E. / de Kock, H.A. / Jonckers, T.H.M. / Peeters, A. / De Meyer, S. / Azijn, H. / Pauwels, R. / de Bethune, M.-P. / King, N.M. / Prabu-Jeyabalan, M. / Schiffer, C.A. / Wigerinck, P.B.T.P.
History
DepositionMay 10, 2004Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 10, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.3Oct 27, 2021Group: Database references / Derived calculations / Structure summary
Category: chem_comp / database_2 ...chem_comp / database_2 / struct_ref_seq_dif / struct_site
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _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
Revision 1.4Aug 23, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Pol Polyprotein
B: Pol Polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,7099
Polymers21,6642
Non-polymers1,0467
Water3,621201
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5800 Å2
ΔGint-52 kcal/mol
Surface area9340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.858, 58.040, 61.656
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Pol Polyprotein


Mass: 10831.750 Da / Num. of mol.: 2 / Fragment: Protease / Mutation: Q7K/K14R/V82T/I84V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Genus: Lentivirus / Gene: POL / Plasmid: PXC34 / Production host: Escherichia coli (E. coli) / Strain (production host): TAP106 / References: UniProt: P35963, HIV-1 retropepsin
#2: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical ChemComp-017 / (3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL(1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE / Darunavir / TMC114 / UIC-94017


Mass: 547.664 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H37N3O7S / Comment: medication*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 201 / 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: 2.1 Å3/Da / Density % sol: 41.44 %
Crystal growTemperature: 280 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: AMMONIUM SULPHATE, SODIUM PHOSPHATE, SODIUM CITRATE, pH 6.2, VAPOR DIFFUSION, HANGING DROP, temperature 280K

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Data collection

DiffractionMean temperature: 210 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.9 Å
DetectorDate: Jun 26, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 1.35→43 Å / Num. all: 39998 / Num. obs: 39998 / % possible obs: 98 % / Observed criterion σ(F): -30 / Observed criterion σ(I): -30 / Redundancy: 6.5 % / Rmerge(I) obs: 0.044 / Net I/σ(I): 13.5

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
REFMAC5refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1F7A

1f7a


Resolution: 1.35→42.26 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.95 / Cross valid method: THROUGHOUT / Stereochemistry target values: Engh & Huber / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20005 1993 5 %RANDOM
Rwork0.16343 ---
obs-37946 --
Displacement parametersBiso mean: 17.869 Å2
Baniso -1Baniso -2Baniso -3
1--0.4 Å20 Å20 Å2
2---0.07 Å20 Å2
3---0.47 Å2
Refinement stepCycle: LAST / Resolution: 1.35→42.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1492 0 66 201 1759
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONr_bond_refined_d0.005
X-RAY DIFFRACTIONr_angle_refined_deg1.3
X-RAY DIFFRACTIONr_mcbond_it1.5
X-RAY DIFFRACTIONr_scbond_it3
LS refinement shellResolution: 1.35→1.385 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.204 146
Rwork0.121 2673

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