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- PDB-4q1y: Mutations Outside the Active Site of HIV-1 Protease Alter Enzyme ... -

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Basic information

Entry
Database: PDB / ID: 4q1y
TitleMutations Outside the Active Site of HIV-1 Protease Alter Enzyme Structure and Dynamic Ensemble of the Active Site to Confer Drug Resistance
Componentsaspartyl proteaseAspartic protease
Keywordshydrolase/hydrolase inhibitor / HIV-1 protease / AIDS / inhibitor complex / hydrolase-hydrolase inhibitor complex
Function / homology
Function and homology information


integrase activity / Integration of viral DNA into host genomic DNA / Autointegration results in viral DNA circles / Minus-strand DNA synthesis / Plus-strand DNA synthesis / Uncoating of the HIV Virion / 2-LTR circle formation / Vpr-mediated nuclear import of PICs / Early Phase of HIV Life Cycle / Integration of provirus ...integrase activity / Integration of viral DNA into host genomic DNA / Autointegration results in viral DNA circles / Minus-strand DNA synthesis / Plus-strand DNA synthesis / Uncoating of the HIV Virion / 2-LTR circle formation / Vpr-mediated nuclear import of PICs / Early Phase of HIV Life Cycle / Integration of provirus / APOBEC3G mediated resistance to HIV-1 infection / Binding and entry of HIV virion / viral life cycle / Assembly Of The HIV Virion / HIV-1 retropepsin / : / Budding and maturation of HIV virion / retroviral ribonuclease H / exoribonuclease H / : / exoribonuclease H activity / protein processing / host multivesicular body / 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 / peptidase 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 / structural molecule activity / host cell plasma membrane / virion membrane / proteolysis / DNA binding / RNA binding / zinc ion binding / membrane / identical protein 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
Chem-017 / ACETATE ION / PHOSPHATE ION / Gag-Pol polyprotein / Pol protein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsRagland, D.A. / Nalam, M.N.L. / Cao, H. / Nalivaika, E.A. / Cai, Y. / Kurt-Yilmaz, N. / Schiffer, C.A.
CitationJournal: J.Am.Chem.Soc. / Year: 2014
Title: Drug resistance conferred by mutations outside the active site through alterations in the dynamic and structural ensemble of HIV-1 protease.
Authors: Ragland, D.A. / Nalivaika, E.A. / Nalam, M.N. / Prachanronarong, K.L. / Cao, H. / Bandaranayake, R.M. / Cai, Y. / Kurt-Yilmaz, N. / Schiffer, C.A.
History
DepositionApr 4, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 18, 2015Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: aspartyl protease
B: aspartyl protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,7379
Polymers21,7282
Non-polymers1,0107
Water2,234124
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5680 Å2
ΔGint-53 kcal/mol
Surface area9280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.813, 58.225, 61.824
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 aspartyl protease / Aspartic protease / Pol protein


Mass: 10863.833 Da / Num. of mol.: 2 / Fragment: unp residues 1-99 / Mutation: Q7K, V32I, L33F
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Strain: HIV-1 M:B_HXB2R / Gene: gag-pol, pol / Plasmid: pXC35 / Production host: Escherichia coli (E. coli) / Strain (production host): Tap56
References: UniProt: V5Y949, UniProt: P04585*PLUS, HIV-1 retropepsin
#2: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


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


Mass: 59.044 Da / Num. of mol.: 3 / 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 / Darunavir


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


Mass: 18.015 Da / Num. of mol.: 124 / 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: 41.56 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: 126mM Phosphate buffer, 63mM Sodium Citrate, 24-29% Ammonium Sulfate, pH 6.2, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 14-BM-C / Wavelength: 0.9002 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 7, 2008 / Details: Bent conical Si-mirror (Rh coated)
RadiationMonochromator: Bent Ge(111) monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9002 Å / Relative weight: 1
ReflectionResolution: 1.5→39.25 Å / Num. all: 29633 / Num. obs: 29633 / % possible obs: 98.8 % / Observed criterion σ(F): 3 / Observed criterion σ(I): 3 / Redundancy: 6.5 % / Rmerge(I) obs: 0.048 / Net I/σ(I): 16.8
Reflection shellResolution: 1.5→1.55 Å / Redundancy: 5 % / % possible all: 96.7

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Processing

Software
NameVersionClassification
REFMAC5.3.0037refinement
ADSCQuantumdata collection
HKL-3000data reduction
HKL-3000data scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→39.25 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.946 / SU B: 2.353 / SU ML: 0.049 / Cross valid method: THROUGHOUT / ESU R: 0.081 / ESU R Free: 0.08 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20737 1497 5.1 %RANDOM
Rwork0.18253 ---
obs0.1838 28079 98.72 %-
all-29773 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 25.341 Å2
Baniso -1Baniso -2Baniso -3
1--1.22 Å20 Å20 Å2
2--1.26 Å20 Å2
3----0.04 Å2
Refinement stepCycle: LAST / Resolution: 1.5→39.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1506 0 65 124 1695
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0221680
X-RAY DIFFRACTIONr_bond_other_d0.0010.021130
X-RAY DIFFRACTIONr_angle_refined_deg1.4972.0192296
X-RAY DIFFRACTIONr_angle_other_deg0.87632789
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2375214
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.32524.91559
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.6515284
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.289158
X-RAY DIFFRACTIONr_chiral_restr0.10.2265
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021852
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02311
X-RAY DIFFRACTIONr_nbd_refined0.1990.2258
X-RAY DIFFRACTIONr_nbd_other0.2040.21189
X-RAY DIFFRACTIONr_nbtor_refined0.1710.2781
X-RAY DIFFRACTIONr_nbtor_other0.0880.2946
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1440.265
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0950.211
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1310.240
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1850.216
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8171.51106
X-RAY DIFFRACTIONr_mcbond_other0.1991.5430
X-RAY DIFFRACTIONr_mcangle_it1.11621694
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.7683694
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.4644.5602
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: 1.501→1.54 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.207 97 -
Rwork0.207 1963 -
obs--94.11 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.8901-0.6172-1.33412.61860.19282.2982-0.1319-0.44720.03430.46330.1155-0.0348-0.08780.07610.01640.0110.04750.0018-0.0102-0.0015-0.107620.869825.868229.414
23.7104-2.6582-0.26343.3410.31023.6035-0.1935-0.0906-0.48880.24570.08770.27810.269-0.10840.1058-0.0125-0.00340.048-0.08020.0213-0.019519.56817.606623.1407
33.44430.62620.2063.1173-0.03151.0774-0.05930.01020.016-0.0004-0.0215-0.1617-0.080.05910.0808-0.02090.0059-0.0058-0.05250.0049-0.044927.914728.484918.7528
44.1698-1.2131-1.00382.4759-0.65013.23680.00720.1894-0.2624-0.1490.03480.1757-0.0881-0.2708-0.042-0.02190.02430.0041-0.04620.0047-0.026812.374526.993618.4056
510.4677-7.24970.90677.54050.47376.9406-0.1245-0.09960.44540.0928-0.1849-0.9546-0.02720.39070.3094-0.0571-0.0255-0.0546-0.05480.05990.101439.538530.431124.0953
627.1103-7.229-1.70388.11312.99236.58640.18330.2923-1.282-0.4361-0.07740.61890.0159-1.1562-0.1058-0.0777-0.04170.02160.1345-0.01510.03890.867721.571818.0701
73.40690.55410.10426.01975.8828.50680.11040.14680.180.08820.3222-1.0335-0.12350.9279-0.4326-0.03990.0083-0.01010.05830.02950.115239.53731.547910.8237
84.3036-2.9531.09520.5791.94582.6766-0.34660.1766-0.2580.03560.83751.38550.0599-0.8309-0.4909-0.01160.0370.04640.25850.20430.05751.034434.257213.6866
910.3693-0.8869-1.06640.8247-0.04782.8535-0.00940.28950.0083-0.1791-0.003-0.03980.0530.05170.0123-0.01110.01670.0227-0.03930.0022-0.059428.111830.53774.1673
1012.3893-5.6499-1.72324.5015-1.59924.3188-0.039-0.07370.16850.15690.2040.0287-0.1859-0.2413-0.165-0.02060.00980.0065-0.05030.0037-0.044112.644139.695111.4204
111.6877-0.0779-1.91863.3155-1.10354.10290.0210.1450.06860.0880.04330.0961-0.1706-0.0015-0.0643-0.0102-0.0139-0.0205-0.0590.0129-0.018829.246633.410314.4311
122.9058-3.0584.09765.4062-4.19596.22540.19510.4007-0.1361-0.3012-0.03820.26940.38590.2143-0.1569-0.04030.0313-0.01230.03960.0027-0.059210.556229.490112.0432
132.515-1.8895-0.623.8693-1.08773.2601-0.0603-0.0389-0.16040.0682-0.0703-0.1908-0.00060.04780.1306-0.02840.00840.0031-0.07130.01220.005428.606719.398219.3915
146.7473-2.5083-3.03464.0498-0.54063.8383-0.1978-0.3304-0.11860.20530.21820.1361-0.1497-0.1243-0.0204-0.00570.05790.03630.00030.0198-0.065911.85829.145827.0784
156.7272-0.96194.91357.9557-11.896121.38850.11060.2178-0.5709-0.5125-0.307-0.2040.69670.70340.1963-0.06620.06730.0791-0.04170.00980.050238.92123.165510.4267
1611.163111.6664-12.337916.797-16.548320.54290.47430.03240.6010.88260.27040.6636-0.8251-0.4495-0.7448-0.05450.18330.08690.04190.10690.00831.841136.882321.1092
1724.05351.105-16.32526.054-1.161430.63460.1237-0.72660.59390.5991-0.0963-0.395-0.12220.4599-0.0274-0.05-0.0298-0.0717-0.09760.00260.042637.43424.025324.6076
1830.7247-31.60713.940839.0739-2.18434.91080.3541.2234-0.6347-0.4731-0.50130.63930.5009-0.00340.14720.00470.05160.02650.06120.0316-0.04292.71423.187824.4778
193.0793-0.72911.19633.2384-2.32078.11760.0821-0.049-0.20010.132-0.105-0.25990.08150.12920.0229-0.063-0.00330.0129-0.07380.03970.047436.377721.46919.3838
201.73931.7417-3.22225.2581-3.76216.0510.02080.12040.00030.16280.11440.1552-0.0392-0.229-0.1352-0.05820.07180.01970.05090.0496-0.02894.043628.708725.3419
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 5
2X-RAY DIFFRACTION1A94 - 99
3X-RAY DIFFRACTION1A6 - 10
4X-RAY DIFFRACTION2B1 - 5
5X-RAY DIFFRACTION2B94 - 99
6X-RAY DIFFRACTION2B6 - 10
7X-RAY DIFFRACTION3A21 - 32
8X-RAY DIFFRACTION4B21 - 32
9X-RAY DIFFRACTION5A11 - 20
10X-RAY DIFFRACTION6B11 - 20
11X-RAY DIFFRACTION7A33 - 43
12X-RAY DIFFRACTION8B33 - 43
13X-RAY DIFFRACTION9A44 - 57
14X-RAY DIFFRACTION10B44 - 57
15X-RAY DIFFRACTION11A77 - 85
16X-RAY DIFFRACTION12B77 - 85
17X-RAY DIFFRACTION13A86 - 93
18X-RAY DIFFRACTION14B86 - 93
19X-RAY DIFFRACTION15A58 - 62
20X-RAY DIFFRACTION16B58 - 62
21X-RAY DIFFRACTION17A63 - 68
22X-RAY DIFFRACTION18B63 - 68
23X-RAY DIFFRACTION19A69 - 76
24X-RAY DIFFRACTION20B69 - 76

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