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- PDB-4q1x: Mutations Outside the Active Site of HIV-1 Protease Alter Enzyme ... -

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Basic information

Entry
Database: PDB / ID: 4q1x
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 / establishment of integrated proviral latency / viral penetration into host nucleus / 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 / PHOSPHATE ION / Gag-Pol polyprotein / Pol protein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 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)22,3945
Polymers21,6602
Non-polymers7353
Water1,67593
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4360 Å2
ΔGint-29 kcal/mol
Surface area9060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.906, 58.277, 61.775
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


Mass: 10829.816 Da / Num. of mol.: 2 / Fragment: unp residues 1-99 / Mutation: Q7K, V32I
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-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
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 93 / 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: 2.12 Å3/Da / Density % sol: 41.85 %
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: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Sep 22, 2008 / Details: OSMIC Mirrors
RadiationMonochromator: OSMIC Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→42.41 Å / Num. all: 14168 / Num. obs: 14168 / % possible obs: 93.86 % / Observed criterion σ(F): 3 / Observed criterion σ(I): 3 / Redundancy: 7.1 % / Rmerge(I) obs: 0.063 / Net I/σ(I): 15.2
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 7.1 % / Num. unique all: 1346 / % possible all: 91.4

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Processing

Software
NameVersionClassification
REFMAC5.3.0037refinement
StructureStudiodata collection
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→42.41 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.927 / SU B: 7.26 / SU ML: 0.109 / Cross valid method: THROUGHOUT / σ(F): 3 / σ(I): 3 / ESU R Free: 0.163 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2341 719 5.1 %RANDOM
Rwork0.1802 ---
obs0.18289 13416 93.86 %-
all-15063 --
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: 27.975 Å2
Baniso -1Baniso -2Baniso -3
1--0.67 Å20 Å20 Å2
2--0.34 Å20 Å2
3---0.33 Å2
Refinement stepCycle: LAST / Resolution: 1.9→42.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1488 0 49 93 1630
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0221604
X-RAY DIFFRACTIONr_bond_other_d0.0010.021073
X-RAY DIFFRACTIONr_angle_refined_deg1.4742.0152193
X-RAY DIFFRACTIONr_angle_other_deg0.85632646
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0925204
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.5725.08857
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.07315261
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.123158
X-RAY DIFFRACTIONr_chiral_restr0.0880.2261
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021756
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02291
X-RAY DIFFRACTIONr_nbd_refined0.1860.2217
X-RAY DIFFRACTIONr_nbd_other0.1970.21101
X-RAY DIFFRACTIONr_nbtor_refined0.170.2733
X-RAY DIFFRACTIONr_nbtor_other0.0840.2901
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.130.271
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1860.28
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1990.245
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1890.212
X-RAY DIFFRACTIONr_mcbond_it0.7071.51064
X-RAY DIFFRACTIONr_mcbond_other0.1761.5420
X-RAY DIFFRACTIONr_mcangle_it0.9621629
X-RAY DIFFRACTIONr_scbond_it1.4753647
X-RAY DIFFRACTIONr_scangle_it2.1334.5564
LS refinement shellResolution: 1.898→1.947 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.385 48 -
Rwork0.212 914 -
obs-914 88.18 %
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)
15.3577-1.7535-0.54336.79251.79343.8655-0.325-0.52130.02740.55780.27860.09480.03080.140.0464-0.02050.04760.00810.00460.0095-0.150820.670825.596629.293
25.58-3.88970.6174.03721.33654.803-0.1273-0.1495-0.50150.1980.17660.36580.16270.0571-0.0494-0.0306-0.00840.0483-0.11260.0396-0.030419.745417.722823.3022
31.32030.34070.19542.7006-0.18031.2932-0.01010.11-0.11050.01520.0615-0.0428-0.03930.0334-0.0514-0.01530.00680.0044-0.0109-0.0048-0.07327.703428.542618.7744
47.084-0.7130.79424.11740.23511.8910.021-0.0378-0.1559-0.18880.00190.153-0.1866-0.0269-0.0229-0.03660.02030.0163-0.08330.0092-0.050912.34626.92918.3074
513.6109-1.307-2.84326.97284.17266.6825-0.0829-0.53960.07480.29050.2428-0.75910.22230.474-0.1599-0.0145-0.0172-0.0806-0.09040.0350.035339.626230.575324.1687
637.6518-19.28380.547717.68383.43065.0684-0.17580.4548-1.37050.0567-0.31231.03050.0538-0.60970.4881-0.0929-0.03860.0125-0.0298-0.01830.03630.917421.441517.8713
79.04260.42891.28158.57363.71717.03390.21470.05950.0279-0.01710.0964-0.6187-0.27520.2865-0.3112-0.0789-0.0030.0032-0.07510.0657-0.03739.772431.742110.4198
810.8581-5.5873-2.928317.10518.05718.77770.160.62530.0911-0.1644-0.17470.66760.1428-0.66520.0147-0.0986-0.01680.031-0.01870.1213-0.06070.506534.399913.2067
912.6442-2.5424-1.41251.16860.47973.1502-0.07950.5791-0.1066-0.1081-0.06320.00380.0415-0.03110.1427-0.0340.02120.0011-0.054-0.0034-0.070727.684731.23814.2623
1013.9579-1.9341-3.31171.9654-1.06222.14890.28710.07440.17120.02240.0470.29760.01130.1337-0.33410.00010.01960.002-0.02590.0162-0.01412.595139.768811.556
110.92030.7099-0.72034.7366-0.48623.9715-0.00510.18920.22290.11430.00350.4076-0.09810.11360.0016-0.0272-0.0302-0.0221-0.00130.028-0.045229.079233.611214.5582
125.2371-4.28284.90047.6981-5.07164.85530.1850.4734-0.1202-0.3058-0.17710.00520.27080.3793-0.0078-0.02050.027-0.00970.03080.0055-0.053910.479529.417511.9354
133.8077-3.3373.0493.196-2.43682.6454-0.00540.1258-0.1605-0.05180.02160.0006-0.0574-0.0638-0.0162-0.0093-0.00220.0097-0.0312-0.0017-0.002428.683419.523519.2074
143.8888-2.1557-2.01321.19761.08481.4163-0.126-0.44210.0243-0.00060.1140.2674-0.1597-0.02390.0120.02290.0530.02920.0118-0.0015-0.030311.656728.812726.9851
152.6144-6.20572.748615.1738-9.086617.70010.13650.3377-0.5269-0.6014-0.6396-0.45810.5280.49450.5031-0.13370.01140.05520.00740.0231-0.012738.978523.517710.3992
1610.814211.0784-9.502618.6181-11.616914.59650.688-0.09431.1070.9577-0.06910.6816-0.7927-0.129-0.6189-0.07870.07230.0165-0.06440.02090.07741.591936.581721.0572
1732.02098.1457-17.893710.8453-6.204237.89290.1113-0.44450.51620.60990.0528-0.31690.02150.9238-0.164-0.0725-0.0126-0.0702-0.1323-0.0167-0.030937.513824.220924.3568
1820.2442-9.8437.143724.8911-0.117316.17340.0530.4935-0.6838-0.0409-0.2173-0.37920.82490.17980.1642-0.064-0.00660.0519-0.09630.0233-0.00252.63822.923.9933
193.3905-0.9511.29892.20570.11978.1482-0.01160.0329-0.16540.0281-0.1614-0.21480.010.30140.173-0.0788-0.0166-0.0007-0.06710.01170.002635.737321.971918.294
206.3521.9749-7.5648.7812-7.80613.9271-0.0079-0.2741-0.0845-0.12940.14130.26280.08760.0363-0.1334-0.14070.0068-0.0356-0.05230.0157-0.03713.951228.491925.2704
211.4919-2.0118-2.968911.74915.09796.04050.05380.0288-0.0134-0.1806-0.03360.0446-0.2634-0.0556-0.0202-0.0090.02630.00050.01830.0132-0.028619.482229.789113.6932
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 DIFFRACTION3A20 - 32
8X-RAY DIFFRACTION4B20 - 32
9X-RAY DIFFRACTION5A11 - 19
10X-RAY DIFFRACTION6B11 - 19
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
25X-RAY DIFFRACTION21A101

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