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- PDB-2ien: Crystal structure analysis of HIV-1 protease with a potent non-pe... -

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Basic information

Entry
Database: PDB / ID: 2ien
TitleCrystal structure analysis of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017)
ComponentsProtease
KeywordsHYDROLASE / HIV-1 protease / dimer / inhibitor / UIC-94017 / TMC114 / darunavir
Function / homology
Function and homology information


HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / host multivesicular body / DNA integration / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency ...HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / host multivesicular body / DNA integration / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency / symbiont-mediated suppression of host gene expression / viral penetration into host nucleus / RNA stem-loop binding / 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 entry into host cell / viral translational frameshifting / lipid binding / host cell nucleus / host cell plasma membrane / structural molecule activity / virion membrane / 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 / RNase H type-1 domain profile. / Ribonuclease H domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Reverse transcriptase (RNA-dependent DNA polymerase) / Retroviral matrix protein / Retrovirus capsid, C-terminal / Retrovirus capsid, N-terminal / zinc finger / Zinc knuckle / Zinc finger, CCHC-type superfamily / Cathepsin D, subunit A; domain 1 / Acid Proteases / Zinc finger, CCHC-type / Zinc finger CCHC-type profile. / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Ribonuclease H superfamily / Aspartic peptidase domain superfamily / Ribonuclease H-like superfamily / Reverse transcriptase/Diguanylate cyclase domain / DNA/RNA polymerase superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-017 / ACETIC ACID / Gag-Pol polyprotein / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.3 Å
AuthorsTie, Y. / Boross, P.I. / Wang, Y.F. / Gaddis, L. / Manna, D. / Hussain, A.K. / Leshchenko, S. / Ghosh, A.K. / Louis, J.M. / Harrison, R.W. / Weber, I.T.
Citation
Journal: J.Mol.Biol. / Year: 2004
Title: High Resolution Crystal Structures of HIV-1 Protease with a Potent Non-Peptide Inhibitor (Uic-94017) Active Against Multi-Drug-Resistant Clinical Strains.
Authors: Tie, Y. / Boross, P.I. / Wang, Y.F. / Gaddis, L. / Hussain, A.K. / Leshchenko, S. / Ghosh, A.K. / Louis, J.M. / Harrison, R.W. / Weber, I.T.
#1: Journal: Antimicrob.Agents Chemother. / Year: 2003
Title: A Novel Bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitors (Pi) Uic-94017 (Tmc114) Potent Against Multi-Pi-Resistant HIV in Vitro
Authors: Koh, Y. / Nakata, H. / Maaeda, K. / Ogata, H. / Bilcer, G. / Devasamudram, T. / Kincaid, J.F. / Boross, P. / Wang, Y.F. / Tie, Y. / Volarath, P. / Gaddis, L. / Harrison, R.W. / Weber, I.T. / ...Authors: Koh, Y. / Nakata, H. / Maaeda, K. / Ogata, H. / Bilcer, G. / Devasamudram, T. / Kincaid, J.F. / Boross, P. / Wang, Y.F. / Tie, Y. / Volarath, P. / Gaddis, L. / Harrison, R.W. / Weber, I.T. / Ghosh, A.K. / Mitsuya, H.
History
DepositionSep 19, 2006Deposition site: RCSB / Processing site: RCSB
SupersessionOct 3, 2006ID: 1S6G
Revision 1.0Oct 3, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.3Oct 18, 2017Group: Refinement description / Category: software
Revision 1.4Oct 20, 2021Group: Database references / Derived calculations / Structure summary
Category: chem_comp / database_2 ...chem_comp / database_2 / pdbx_struct_conn_angle / struct_conn / 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 / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_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
Revision 1.5Aug 30, 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

Downloads & links

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Assembly

Deposited unit
A: Protease
B: Protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,42710
Polymers21,4812
Non-polymers9468
Water4,432246
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5440 Å2
ΔGint-56 kcal/mol
Surface area9370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.260, 85.910, 46.051
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Protease / Retropepsin


Mass: 10740.677 Da / Num. of mol.: 2 / Fragment: residues 500-598
Mutation: Q7K, L33I, L63I, C67A, C95A, Q107K, L133I, L163I, C167A, C195A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Genus: Lentivirus / Gene: gag, pol / Plasmid: PET11A / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P03368, UniProt: P03367*PLUS, HIV-1 retropepsin

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Non-polymers , 6 types, 254 molecules

#2: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-ACY / ACETIC ACID


Mass: 60.052 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H4O2
#5: 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, antiretroviral*YM
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 246 / 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: 2.68 Å3/Da / Density % sol: 54.12 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 4.8
Details: sodium chloride, sodium acetate, DMSO, dioxane, pH 4.80, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 90 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1
DetectorType: MARRESEARCH / Detector: CCD / Date: Dec 12, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.3→50 Å / Num. obs: 56890 / % possible obs: 98.6 % / Observed criterion σ(I): 3 / Redundancy: 8.5 % / Rmerge(I) obs: 0.065 / Net I/σ(I): 17.3
Reflection shellResolution: 1.3→1.35 Å / Rmerge(I) obs: 0.268 / % possible all: 90.2

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Processing

Software
NameClassification
AMoREphasing
SHELXL-97refinement
MAR345data collection
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1FG6

1fg6


Resolution: 1.3→10 Å / Num. parameters: 18161 / Num. restraintsaints: 23618 / Cross valid method: THROUGHOUT / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.205 2831 5 %RANDOM
Rwork0.173 ---
all0.202 ---
obs0.202 56687 98.6 %-
Refine analyzeNum. disordered residues: 37 / Occupancy sum hydrogen: 1632.71 / Occupancy sum non hydrogen: 1759.89
Refinement stepCycle: LAST / Resolution: 1.3→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 61 246 1819
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONs_bond_d0.014
X-RAY DIFFRACTIONs_angle_d0.038
X-RAY DIFFRACTIONs_similar_dist0
X-RAY DIFFRACTIONs_from_restr_planes0.031
X-RAY DIFFRACTIONs_zero_chiral_vol0.073
X-RAY DIFFRACTIONs_non_zero_chiral_vol0.108
X-RAY DIFFRACTIONs_anti_bump_dis_restr0.034
X-RAY DIFFRACTIONs_rigid_bond_adp_cmpnt0.004
X-RAY DIFFRACTIONs_similar_adp_cmpnt0.038
X-RAY DIFFRACTIONs_approx_iso_adps0.096

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