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- PDB-3s85: Discovery of New HIV Protease Inhibitors with Potential for Conve... -

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Basic information

Entry
Database: PDB / ID: 3s85
TitleDiscovery of New HIV Protease Inhibitors with Potential for Convenient Dosing and Reduced Side Effects: A-790742 and A-792611.
ComponentsProtease/reverse transcriptase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Beta Barrel / Acid protease / Aspartic-type endopepidase activity / HYDROLASE-HYDROLASE INHIBITOR complex
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 / endonuclease activity / 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 / metal ion binding
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
METHYL N-[(2S)-1-[[(2S,3S,5S)-5-[[(2S)-2-(METHOXYCARBONYLAMINO)-3,3-DIMETHYL-BUTANOYL]AMINO]-3-OXIDANYL-6-PHENYL-1-(4-PYRIDIN-3-YLPHENYL)HEXAN-2-YL]AMINO]-3,3-DIMETHYL-1-OXIDANYLIDENE-BUTAN-2-YL]CARBAMATE / Chem-LK0 / Gag-Pol polyprotein / Protease
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsDeGoey, D.A. / Flosi, W.J. / Grampovnik, D.J. / Flentge, C.A.
CitationJournal: J.Med.Chem. / Year: 2009
Title: 2-Pyridyl P1'-substituted symmetry-based human immunodeficiency virus protease inhibitors (A-792611 and A-790742) with potential for convenient dosing and reduced side effects.
Authors: Degoey, D.A. / Grampovnik, D.J. / Flentge, C.A. / Flosi, W.J. / Chen, H.J. / Yeung, C.M. / Randolph, J.T. / Klein, L.L. / Dekhtyar, T. / Colletti, L. / Marsh, K.C. / Stoll, V. / Mamo, M. / ...Authors: Degoey, D.A. / Grampovnik, D.J. / Flentge, C.A. / Flosi, W.J. / Chen, H.J. / Yeung, C.M. / Randolph, J.T. / Klein, L.L. / Dekhtyar, T. / Colletti, L. / Marsh, K.C. / Stoll, V. / Mamo, M. / Morfitt, D.C. / Nguyen, B. / Schmidt, J.M. / Swanson, S.J. / Mo, H. / Kati, W.M. / Molla, A. / Kempf, D.J.
History
DepositionMay 27, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 11, 2012Provider: repository / Type: Initial release
Revision 1.1Dec 12, 2012Group: Other
Revision 1.2Feb 28, 2024Group: 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 / struct_ncs_dom_lim / 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_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_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id / _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/reverse transcriptase
B: Protease/reverse transcriptase
C: Protease/reverse transcriptase
D: Protease/reverse transcriptase
E: Protease/reverse transcriptase
F: Protease/reverse transcriptase
G: Protease/reverse transcriptase
H: Protease/reverse transcriptase
I: Protease/reverse transcriptase
J: Protease/reverse transcriptase
K: Protease/reverse transcriptase
L: Protease/reverse transcriptase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)134,19318
Polymers129,96912
Non-polymers4,2236
Water0
1
A: Protease/reverse transcriptase
B: Protease/reverse transcriptase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3653
Polymers21,6622
Non-polymers7041
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3590 Å2
ΔGint-23 kcal/mol
Surface area10110 Å2
MethodPISA
2
C: Protease/reverse transcriptase
D: Protease/reverse transcriptase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3653
Polymers21,6622
Non-polymers7041
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3570 Å2
ΔGint-23 kcal/mol
Surface area9950 Å2
MethodPISA
3
E: Protease/reverse transcriptase
F: Protease/reverse transcriptase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3653
Polymers21,6622
Non-polymers7041
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3560 Å2
ΔGint-22 kcal/mol
Surface area9920 Å2
MethodPISA
4
G: Protease/reverse transcriptase
H: Protease/reverse transcriptase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3653
Polymers21,6622
Non-polymers7041
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3650 Å2
ΔGint-24 kcal/mol
Surface area10010 Å2
MethodPISA
5
I: Protease/reverse transcriptase
J: Protease/reverse transcriptase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3653
Polymers21,6622
Non-polymers7041
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3640 Å2
ΔGint-24 kcal/mol
Surface area10130 Å2
MethodPISA
6
K: Protease/reverse transcriptase
L: Protease/reverse transcriptase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3653
Polymers21,6622
Non-polymers7041
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3680 Å2
ΔGint-24 kcal/mol
Surface area9870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.478, 66.512, 87.595
Angle α, β, γ (deg.)110.41, 91.49, 93.64
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12C
22D
13E
23F
14G
24H
15I
25J
16K
26L

NCS domain segments:

Component-ID: 1 / Beg auth comp-ID: PRO / Beg label comp-ID: PRO / End auth comp-ID: PHE / End label comp-ID: PHE / Refine code: 4 / Auth seq-ID: 1 - 99 / Label seq-ID: 1 - 99

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11AA
21BB
12CC
22DD
13EE
23FF
14GG
24HH
15II
25JJ
16KK
26LL

NCS ensembles :
ID
1
2
3
4
5
6

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Components

#1: Protein
Protease/reverse transcriptase


Mass: 10830.781 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: pol / Production host: Escherichia coli (E. coli) / References: UniProt: Q9QIQ7, UniProt: P12497*PLUS
#2: Chemical
ChemComp-LK0 / methyl N-[(2S)-1-[[(2S,3S,5S)-5-[[(2S)-2-(methoxycarbonylamino)-3,3-dimethyl-butanoyl]amino]-3-oxidanyl-6-phenyl-1-(4-pyridin-3-ylphenyl)hexan-2-yl]amino]-3,3-dimethyl-1-oxidanylidene-butan-2-yl]carbamate


Type: peptide-like, Peptide-like / Class: Enzyme inhibitor / Mass: 703.867 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C39H53N5O7
References: METHYL N-[(2S)-1-[[(2S,3S,5S)-5-[[(2S)-2-(METHOXYCARBONYLAMINO)-3,3-DIMETHYL-BUTANOYL]AMINO]-3-OXIDANYL-6-PHENYL-1-(4-PYRIDIN-3-YLPHENYL)HEXAN-2-YL]AMINO]-3,3-DIMETHYL-1-OXIDANYLIDENE-BUTAN-2-YL]CARBAMATE

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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: 2.49 Å3/Da / Density % sol: 50.61 %
Crystal growTemperature: 297 K / Method: vapor diffusion, hanging drop / pH: 5.2
Details: 0.3-0.7M Sodium chloride, Na acetate, pH 5.4, VAPOR DIFFUSION, HANGING DROP, temperature 297K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID
DetectorType: ADSC QUANTUM 210 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.8→50 Å / Num. obs: 58085 / % possible obs: 96.4 % / Redundancy: 1.1 % / Biso Wilson estimate: 60.4 Å2 / Rmerge(I) obs: 0.088 / Net I/σ(I): 9.2

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
PHASESphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→50 Å / Cor.coef. Fo:Fc: 0.901 / Cor.coef. Fo:Fc free: 0.849 / SU B: 19.468 / SU ML: 0.374 / Cross valid method: THROUGHOUT / ESU R Free: 0.474 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28515 1500 5 %RANDOM
Rwork0.2346 ---
obs0.23719 28293 96.55 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 37 Å2
Baniso -1Baniso -2Baniso -3
1-0.77 Å20.88 Å2-0.78 Å2
2--2.37 Å21.55 Å2
3----1.99 Å2
Refinement stepCycle: LAST / Resolution: 2.8→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9120 0 306 0 9426
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0229594
X-RAY DIFFRACTIONr_angle_refined_deg1.0092.02213020
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.93951176
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.64225336
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.957151704
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.5841548
X-RAY DIFFRACTIONr_chiral_restr0.0580.21530
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.027128
X-RAY DIFFRACTIONr_nbd_refined0.1740.23906
X-RAY DIFFRACTIONr_nbtor_refined0.3020.26352
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1080.2285
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1770.2145
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1220.29
X-RAY DIFFRACTIONr_mcbond_it0.2561.56061
X-RAY DIFFRACTIONr_mcangle_it0.45129516
X-RAY DIFFRACTIONr_scbond_it0.38333985
X-RAY DIFFRACTIONr_scangle_it0.6714.53504
Refine LS restraints NCS

Dom-ID: 1 / Number: 760 / Refine-ID: X-RAY DIFFRACTION

Ens-IDAuth asym-IDTypeRms dev position (Å)Weight position
1Amedium positional0.380.5
2Cmedium positional0.380.5
3Emedium positional0.370.5
4Gmedium positional0.380.5
5Imedium positional0.40.5
6Kmedium positional0.490.5
1Amedium thermal0.292
2Cmedium thermal0.222
3Emedium thermal0.22
4Gmedium thermal0.232
5Imedium thermal0.292
6Kmedium thermal0.592
LS refinement shellResolution: 2.8→2.873 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.452 90 -
Rwork0.353 1956 -
obs--90.41 %

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