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- PDB-5aha: Disubstituted bis-THF moieties as new P2 ligands in non-peptidal ... -

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Basic information

Entry
Database: PDB / ID: 5aha
TitleDisubstituted bis-THF moieties as new P2 ligands in non-peptidal HIV- 1 Protease Inhibitors (II)
ComponentsPROTEASE
KeywordsHYDROLASE / INHIBITOR / RATIONAL DRUG DESIGN / BIS-THF BIS-DIOL
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 penetration into host nucleus ...: / : / HIV-1 retropepsin / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / host multivesicular body / DNA integration / RNA-directed DNA polymerase / viral penetration into host nucleus / viral genome integration into host DNA / establishment of integrated proviral latency / RNA-directed DNA polymerase activity / RNA-DNA hybrid ribonuclease activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / 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 / host cell plasma membrane / virion membrane / structural molecule activity / proteolysis / DNA binding / RNA 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. / 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 / 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-ZLP / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHUMAN IMMUNODEFICIENCY VIRUS TYPE 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.35 Å
AuthorsHohlfeld, K. / Wegner, J.K. / Kesteleyn, B. / Linclau, B. / Unge, J.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Disubstituted Bis-Thf Moieties as New P2 Ligands in Non-Peptidal HIV-1 Protease Inhibitors (II).
Authors: Hohlfeld, K. / Wegner, J. / Kesteleyn, B. / Linclau, B. / Unge, J.
History
DepositionFeb 5, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 6, 2015Provider: repository / Type: Initial release
Revision 1.1May 27, 2015Group: Database references
Revision 1.2Jan 17, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.3May 1, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_sheet / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_sheet.number_strands / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AB" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AB" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL. THE SHEETS PRESENTED AS "BA" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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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)22,3346
Polymers21,5512
Non-polymers7834
Water5,062281
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5370 Å2
ΔGint-49.2 kcal/mol
Surface area9230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.376, 85.958, 46.436
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein PROTEASE /


Mass: 10775.659 Da / Num. of mol.: 2 / Fragment: ASPARTYL PROTEASE, RESIDUES 501-599 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 (Z2/CDC-Z34 ISOLATE)
Strain: 99HHP1 (D10) / Plasmid: PEXP5 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(AI) / References: UniProt: P03366, HIV-1 retropepsin
#2: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-ZLP / (3R,3aS,4R,6aR)-4-(2-methoxyethoxy)hexahydrofuro[2,3-b]furan-3-yl {(2S,3R)-3-hydroxy-4-[{[(2Z)-2-(methylimino)-2,3-dihydro-1,3-benzoxazol-6-yl]sulfonyl}(2-methylpropyl)amino]-1-phenylbutan-2-yl}carbamate


Mass: 676.778 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H44N4O10S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 281 / 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: 2.7 Å3/Da / Density % sol: 54.49 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: MAX II / Beamline: I911-3 / Wavelength: 1
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Apr 17, 2012 / Details: MIRRORS
RadiationMonochromator: SI / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.35→58.4 Å / Num. obs: 52307 / % possible obs: 100 % / Observed criterion σ(I): 4 / Redundancy: 6.2 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 5.8
Reflection shellResolution: 1.35→1.42 Å / Redundancy: 5.2 % / Rmerge(I) obs: 0.39 / Mean I/σ(I) obs: 1.7 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
iMOSFLMdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NON-PUBLISHED

Resolution: 1.35→48.29 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.941 / SU B: 0.878 / SU ML: 0.037 / Cross valid method: THROUGHOUT / ESU R: 0.061 / ESU R Free: 0.06 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.22494 2622 5 %RANDOM
Rwork0.20888 ---
obs0.2097 49634 99.71 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 15.778 Å2
Baniso -1Baniso -2Baniso -3
1-0.11 Å20 Å20 Å2
2---0.26 Å20 Å2
3---0.15 Å2
Refinement stepCycle: LAST / Resolution: 1.35→48.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 50 281 1843
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0221645
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1922.0522239
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8595197
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.67124.81554
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.54115278
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.098158
X-RAY DIFFRACTIONr_chiral_restr0.0980.2262
X-RAY DIFFRACTIONr_gen_planes_refined0.0210.0211162
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_it1.891.5981
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it3.38521596
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it5.5343664
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it8.0044.5642
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: 1.347→1.382 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.295 175 -
Rwork0.264 3517 -
obs--96.35 %

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