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- PDB-1d4k: HIV-1 PROTEASE COMPLEXED WITH A MACROCYCLIC PEPTIDOMIMETIC INHIBITOR -

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Basic information

Entry
Database: PDB / ID: 1d4k
TitleHIV-1 PROTEASE COMPLEXED WITH A MACROCYCLIC PEPTIDOMIMETIC INHIBITOR
ComponentsHIV-1 PROTEASE
KeywordsHYDROLASE / HIV / PROTEASE / INHIBITOR / ANTIVIRAL
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 genome integration into host DNA ...HIV-1 retropepsin / : / retroviral ribonuclease H / exoribonuclease H / : / exoribonuclease H activity / host multivesicular body / DNA integration / RNA-directed DNA polymerase / viral genome integration into host DNA / viral penetration into host nucleus / establishment of integrated proviral latency / RNA-directed DNA polymerase activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / RNA-DNA hybrid ribonuclease activity / 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. / Ribonuclease H superfamily / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / 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-PI8 / Gag-Pol polyprotein
Similarity search - Component
MethodX-RAY DIFFRACTION / Resolution: 1.85 Å
AuthorsTyndall, J.D. / Reid, R.C. / Tyssen, D.P. / Jardine, D.K. / Todd, B. / Passmore, M. / March, D.R. / Pattenden, L.K. / Alewood, D. / Hu, S.H. ...Tyndall, J.D. / Reid, R.C. / Tyssen, D.P. / Jardine, D.K. / Todd, B. / Passmore, M. / March, D.R. / Pattenden, L.K. / Alewood, D. / Hu, S.H. / Alewood, P.F. / Birch, C.J. / Martin, J.L. / Fairlie, D.P.
Citation
Journal: J.Med.Chem. / Year: 2000
Title: Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease.
Authors: Tyndall, J.D. / Reid, R.C. / Tyssen, D.P. / Jardine, D.K. / Todd, B. / Passmore, M. / March, D.R. / Pattenden, L.K. / Bergman, D.A. / Alewood, D. / Hu, S.H. / Alewood, P.F. / Birch, C.J. / ...Authors: Tyndall, J.D. / Reid, R.C. / Tyssen, D.P. / Jardine, D.K. / Todd, B. / Passmore, M. / March, D.R. / Pattenden, L.K. / Bergman, D.A. / Alewood, D. / Hu, S.H. / Alewood, P.F. / Birch, C.J. / Martin, J.L. / Fairlie, D.P.
#1: Journal: Biochemistry / Year: 1999
Title: Molecular Recognition of Macrocyclic Peptidomimetic Inhibitors by HIV-1 Protease.
Authors: Martin, J.L. / Begun, J. / Schindeler, A. / Wickramasinghe, W.A. / Alewood, D. / Alewood, P.F. / Bergman, D.A. / Brinkworth, R.I. / Abbenante, G. / March, D.R. / Reid, R.C. / Fairlie, D.P.
#2: Journal: J.Am.Chem.Soc. / Year: 1996
Title: Substrate-Based Cyclic Peptidomimetics Of Phe Ile Val That Inhibit HIV-1 Protease Using a Novel Enzyme Binding Mode
Authors: March, D.R. / Abbenante, G. / Bergman, D. / Brinkworth, R.I. / Wickramasinghe, W. / Begun, J. / Martin, J.L. / Fairlie, D.P.
#3: Journal: J.Am.Chem.Soc. / Year: 1995
Title: Regioselective Structural and Functional Mimicry Of Peptides: Design Of Hydrolytically Stable Cyclic Peptidomimetic Inhibitors Of HIV-1 Protease.
Authors: Abbenante, G. / March, D. / Bergman, D. / Hunt, P.A. / Garnham, B. / Dancer, R.J. / Martin, J.L. / Fairlie, D.P.
History
DepositionOct 4, 1999Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 11, 2000Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 4, 2017Group: Refinement description / Category: software
Revision 1.4Nov 3, 2021Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / struct_conn / 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_conn.pdbx_leaving_atom_flag / _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: HIV-1 PROTEASE
B: HIV-1 PROTEASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,4225
Polymers21,5312
Non-polymers8913
Water1,60389
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5460 Å2
ΔGint-42 kcal/mol
Surface area8850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.820, 58.920, 61.860
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 HIV-1 PROTEASE /


Mass: 10765.687 Da / Num. of mol.: 2 / Mutation: Q7K, L33I, C67(ABA), C95(ABA) / Source method: obtained synthetically
Details: SF2 isolate, chemically synthesised protein corresponds to the protease from HIV-1, with 4 mutations per monomer
References: UniProt: P03369, HIV-1 retropepsin
#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-PI8 / N-13-[(10S,13S)-9,12-DIOXO-10-(2-BUTYL)-2-OXA-8,11-DIAZABICYCLO [13.2.2] NONADECA-15,17,18-TRIENE] (2R)-BENZYL-(4S)-HYDROXY-5-AMINOPENTANOIC (1R)-HYDROXY-(2S)-INDANEAMIDE / MACROCYCLIC PEPTIDOMIMETIC INHIBITOR 8


Mass: 698.891 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C41H54N4O6
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 89 / 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: 2.19 Å3/Da / Density % sol: 43.88 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: ammonium sulfate. acetate buffer, , pH 5.5, VAPOR DIFFUSION, HANGING DROP, temperature 293.0K
Crystal grow
*PLUS
Temperature: 20 ℃ / Details: inhibitor:protein molar ratio is 10:1
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
15 mg/mlprotein1drop
30.1 Macetate1reservoir
435-60 %satammonium sulfate1reservoir
2inhibitor1dropin DMSO

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.54
DetectorType: RIGAKU RAXIS IIC / Detector: IMAGE PLATE / Date: Aug 17, 1998
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. all: 55326 / Num. obs: 51287 / % possible obs: 92.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 1 / Redundancy: 3.56 % / Biso Wilson estimate: 13 Å2 / Rmerge(I) obs: 0.051 / Net I/σ(I): 12
Reflection shellResolution: 1.85→1.92 Å / Redundancy: 8.19 % / Rmerge(I) obs: 0.277 / Num. unique all: 1457 / % possible all: 87.9
Reflection
*PLUS
Num. obs: 15546 / Num. measured all: 51287
Reflection shell
*PLUS
% possible obs: 87.9 %

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Processing

Software
NameVersionClassification
X-PLORmodel building
X-PLOR3.851refinement
DENZOdata reduction
SCALEPACKdata scaling
X-PLORphasing
RefinementResolution: 1.85→8 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 10000000 / Data cutoff low absF: 0.001 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.259 1547 10.1 %RANDOM
Rwork0.212 ---
all0.2119 15323 --
obs0.212 15323 93 %-
Displacement parametersBiso mean: 24.5 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.26 Å0.23 Å
Luzzati d res low-5 Å
Luzzati sigma a0.23 Å0.24 Å
Refinement stepCycle: LAST / Resolution: 1.85→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1530 0 68 89 1687
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONx_bond_d0.005
X-RAY DIFFRACTIONx_bond_d_na
X-RAY DIFFRACTIONx_bond_d_prot
X-RAY DIFFRACTIONx_angle_d
X-RAY DIFFRACTIONx_angle_d_na
X-RAY DIFFRACTIONx_angle_d_prot
X-RAY DIFFRACTIONx_angle_deg1.2
X-RAY DIFFRACTIONx_angle_deg_na
X-RAY DIFFRACTIONx_angle_deg_prot
X-RAY DIFFRACTIONx_dihedral_angle_d27.1
X-RAY DIFFRACTIONx_dihedral_angle_d_na
X-RAY DIFFRACTIONx_dihedral_angle_d_prot
X-RAY DIFFRACTIONx_improper_angle_d1.12
X-RAY DIFFRACTIONx_improper_angle_d_na
X-RAY DIFFRACTIONx_improper_angle_d_prot
X-RAY DIFFRACTIONx_mcbond_it1.411.5
X-RAY DIFFRACTIONx_mcangle_it2.32
X-RAY DIFFRACTIONx_scbond_it2.412
X-RAY DIFFRACTIONx_scangle_it3.882.5
LS refinement shellResolution: 1.85→1.96 Å / Rfactor Rfree error: 0.02 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.316 253 10.6 %
Rwork0.285 2133 -
obs--88.3 %
Software
*PLUS
Name: X-PLOR / Version: 3.851 / Classification: refinement
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_angle_deg1.16
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_deg27.1
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_deg1.12
LS refinement shell
*PLUS
Rfactor Rfree: 0.312 / Rfactor Rwork: 0.288

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