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- PDB-1fko: CRYSTAL STRUCTURE OF NNRTI RESISTANT K103N MUTANT HIV-1 REVERSE T... -

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Entry
Database: PDB / ID: 1fko
TitleCRYSTAL STRUCTURE OF NNRTI RESISTANT K103N MUTANT HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH DMP-266(EFAVIRENZ)
Components
  • HIV-1 RT, A-CHAIN
  • HIV-1 RT, B-CHAIN
KeywordsTRANSFERASE / HIV-1 reverse transcriptase / AIDS / non-nucleoside inhibitor / DMP-266 / Efavirenz / drug resistance mutation / drug design
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 / HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / Assembly Of The HIV Virion / Budding and maturation of HIV virion / host multivesicular body / protein processing / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency / viral penetration into host nucleus / RNA stem-loop binding / RNA-directed DNA polymerase activity / RNA-DNA hybrid ribonuclease activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / peptidase activity / host cell / viral nucleocapsid / DNA recombination / DNA-directed DNA polymerase / aspartic-type endopeptidase activity / Hydrolases; Acting on ester bonds / DNA-directed DNA polymerase activity / symbiont-mediated suppression of host gene expression / viral translational frameshifting / lipid binding / symbiont entry into host cell / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / DNA binding / zinc ion binding / identical protein binding / membrane
Similarity search - Function
HIV Type 1 Reverse Transcriptase, subunit A, domain 1 / HIV Type 1 Reverse Transcriptase; Chain A, domain 1 / Reverse transcriptase/Diguanylate cyclase domain / Ribonuclease H-like superfamily/Ribonuclease H / Reverse transcriptase connection / Reverse transcriptase connection domain / Reverse transcriptase thumb / Reverse transcriptase thumb domain / Integrase Zinc binding domain / Zinc finger integrase-type profile. ...HIV Type 1 Reverse Transcriptase, subunit A, domain 1 / HIV Type 1 Reverse Transcriptase; Chain A, domain 1 / Reverse transcriptase/Diguanylate cyclase domain / Ribonuclease H-like superfamily/Ribonuclease H / 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. / Retropepsin-like catalytic domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / RNase H type-1 domain profile. / Ribonuclease H domain / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Reverse transcriptase domain / Retrovirus capsid, C-terminal / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase (RT) catalytic domain profile. / Retroviral matrix protein / Retrovirus capsid, N-terminal / zinc finger / Zinc knuckle / Zinc finger, CCHC-type superfamily / Zinc finger, CCHC-type / Zinc finger CCHC-type profile. / Nucleotidyltransferase; domain 5 / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Ribonuclease H superfamily / Ribonuclease H-like superfamily / Reverse transcriptase/Diguanylate cyclase domain / Alpha-Beta Plaits / Roll / DNA/RNA polymerase superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-EFZ / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.9 Å
AuthorsRen, J. / Milton, J. / Weaver, K.L. / Short, S.A. / Stuart, D.I. / Stammers, D.K.
Citation
Journal: Structure Fold.Des. / Year: 2000
Title: Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase.
Authors: Ren, J. / Milton, J. / Weaver, K.L. / Short, S.A. / Stuart, D.I. / Stammers, D.K.
#1: Journal: J.Biol.Chem. / Year: 2000
Title: Binding of the second generattion non-nucleoside inhibitor S-1153 to HIV-1 reverse transcriptase involves extensive main chain hydrogen bonding
Authors: Ren, J. / Nichols, C. / Bird, L.E. / Fujiwara, T. / Suginoto, H. / Stuart, D.I. / Stammers, D.K.
#2: Journal: J.Biol.Chem. / Year: 2000
Title: Phenethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases: structural and biochemical analyses
Authors: Ren, J. / Diprose, J. / Warren, J. / Esnouf, R.M. / Bird, L.E. / Ikemizu, S. / Slater, M. / Milton, J. / Balzarini, J. / Stuart, D.I. / Stammers, D.K.
#3: Journal: J.Med.Chem. / Year: 1999
Title: Crystallographic analysis of the binding modes of non-nucleoside thiazoloisoindolinone inhibitors to HIV-1 reverse transcriptase and comparison with modeling studies
Authors: Ren, J. / Esnouf, R.M. / Hopkins, A.L. / Stuart, D.I. / Stammers, D.K.
#4: Journal: J.Med.Chem. / Year: 1999
Title: Design of MKC-442 (emivirine) analogues with improved activity against drug-resistant HIV mutants
Authors: Hopkins, A.L. / Ren, J. / Tanaka, H. / Baba, M. / Okamato, M. / Stuart, D.I. / Stammers, D.K.
#5: Journal: Biochemistry / Year: 1998
Title: Crystal structures of reverse transcriptase in complex with carboxanilide derivatives
Authors: Ren, J. / Esnouf, R.M. / Hopkins, A.L. / Warren, J. / Balzarini, J. / Stuart, D.I. / Stammers, D.K.
#6: Journal: Proc.Natl.Acad.Sci.USA / Year: 1998
Title: 3'-azido-3'-deoxythymidine drug resistance mutations in HIV-1 reverse transcriptase can induce long range conformational changes
Authors: Ren, J. / Esnouf, R.M. / Hopkins, A.L. / Jones, E.Y. / Kirby, I. / Keeling, J. / Ross, C.K. / Larder, B.A. / Stuart, D.I. / Stammers, D.K.
#7: Journal: Acta Crystallogr.,Sect.D / Year: 1998
Title: Continuous and discontinuous changes in the unit cell of HIV-1 reverse transcriptase crystals on dehydration
Authors: Esnouf, R.M. / Ren, J. / Garman, E. / Somers, D.O. / Ross, C.K. / Jones, E.Y. / K Stammers, D. / Stuart, D.I.
#8: Journal: Proc.Natl.Acad.Sci.USA / Year: 1997
Title: Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this non-nucleoside inhibitor
Authors: Esnouf, R.M. / Ren, J. / Hopkins, A.L. / Ross, C.K. / Jones, E.Y. / Stammers, D.K. / Stuart, D.I.
#9: Journal: J.Med.Chem. / Year: 1996
Title: Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors
Authors: L Hopkins, A. / Ren, J. / Esnouf, R.M. / Willcox, B.E. / Jones, E.Y. / Ross, C.K. / Miyasaka, T. / Walker, R.T. / Tanaka, H. / Stammers, D.K. / Stuart, D.I.
#10: Journal: Structure / Year: 1995
Title: The structure of HIV-1 reverse transcriptase complexed with 9-chloro-TIBO: lessons for inhibitor design
Authors: Ren, J. / Esnouf, R.M. / Hopkins, A.L. / Ross, C.K. / Jones, E.Y. / K Stammers, D. / Stuart, D.I.
#11: Journal: Nat.Struct.Biol. / Year: 1995
Title: High Resolution Structures of HIV-1 RT From Four RT-inhibitor Complexes
Authors: Ren, J. / Esnouf, R.M. / Garman, E. / Somers, D.O. / Ross, C.K. / Kirby, I. / Keeling, J. / Darby, G. / Jones, E.Y. / Stuart, D.I. / Stammers, D.K.
#12: Journal: Nat.Struct.Biol. / Year: 1995
Title: Mechanism of Inhibition of HIV-1 Reverse Transcriptase by Non-nucleoside Inhibitors
Authors: Esnouf, R.M. / Ren, J. / Ross, C.K. / Jones, E.Y. / Stammers, D.K. / Stuart, D.I.
#13: Journal: J.Mol.Biol. / Year: 1994
Title: Crystals of HIV-1 Reverse Transcriptase Diffracting to 2.2 Angstrom Resolution
Authors: Stammers, D.K. / Somers, D.O. / Ross, C.K. / Kirby, I. / Ray, P.H. / Wilson, J.E. / Norman, M. / Ren, J. / Esnouf, R.M. / Garman, E. / Jones, E.Y. / Stuart, D.I.
History
DepositionAug 10, 2000Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 3, 2000Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jul 18, 2012Group: Non-polymer description
Revision 1.4Jan 31, 2018Group: Database references / Category: citation_author / Item: _citation_author.name
Revision 1.5Mar 14, 2018Group: Database references / Category: struct_ref_seq_dif / Item: _struct_ref_seq_dif.details
Revision 1.6Oct 30, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / 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

Downloads & links

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Assembly

Deposited unit
A: HIV-1 RT, A-CHAIN
B: HIV-1 RT, B-CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,4683
Polymers114,1532
Non-polymers3161
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5920 Å2
ΔGint-34 kcal/mol
Surface area46060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)140.3, 109.7, 74.4
Angle α, β, γ (deg.)90, 90, 90
Int Tables number19
Space group name H-MP212121
DetailsHIV-1 RT is a heterodimer consisting of a p66 and a p51 subunits, the p51 contains the first 440 residues of the p66.

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Components

#1: Protein HIV-1 RT, A-CHAIN


Mass: 62768.746 Da / Num. of mol.: 1 / Fragment: P66 / Mutation: L103N
Source method: isolated from a genetically manipulated source
Details: COMPLEXED WITH DMP-266(EFAVIRENZ) / Source: (gene. exp.) Human immunodeficiency virus 1 / Genus: Lentivirus / Strain: HXB2 ISOLATE / Production host: Escherichia coli (E. coli) / References: UniProt: P04585, RNA-directed DNA polymerase
#2: Protein HIV-1 RT, B-CHAIN


Mass: 51383.969 Da / Num. of mol.: 1 / Fragment: P51 / Mutation: L103N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Genus: Lentivirus / Strain: HXB2 ISOLATE / Production host: Escherichia coli (E. coli) / References: UniProt: P04585, RNA-directed DNA polymerase
#3: Chemical ChemComp-EFZ / (-)-6-CHLORO-4-CYCLOPROPYLETHYNYL-4-TRIFLUOROMETHYL-1,4-DIHYDRO-2H-3,1-BENZOXAZIN-2-ONE / DMP-266 / Efavirenz


Mass: 315.675 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H9ClF3NO2
Has protein modificationY

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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: 2.51 Å3/Da / Density % sol: 50.95 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5
Details: see reference 13, pH 5, VAPOR DIFFUSION, SITTING DROP, temperature 277K
Crystal grow
*PLUS
Temperature: 4 ℃ / pH: 5 / Details: Ren, J., (1998) Proc.Natl.Acad.Sci.USA, 95, 9518.
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-ID
126 mg/mlenzyme1drop
26 %(w/v)PEG34001drop
46 %(w/v)PEG1reservoir
3citrate/phosphate1drop

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Data collection

DiffractionMean temperature: 289 K
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-6A / Wavelength: 1
DetectorType: FUJI / Detector: IMAGE PLATE / Date: Nov 30, 1997
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.9→30 Å / Num. obs: 23338 / % possible obs: 89.2 % / Observed criterion σ(I): -1.5 / Redundancy: 3.4 % / Biso Wilson estimate: 55.6 Å2 / Rmerge(I) obs: 0.118 / Net I/σ(I): 6.6
Reflection shellResolution: 2.9→3 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.641 / Num. unique all: 2006 / % possible all: 75.3
Reflection
*PLUS
Lowest resolution: 30 Å / Num. measured all: 83108
Reflection shell
*PLUS
% possible obs: 75.3 % / Num. unique obs: 2006

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Processing

Software
NameClassification
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
CNSphasing
RefinementResolution: 2.9→30 Å / σ(F): 0 / Stereochemistry target values: Engh & Huber
Details: positional restraints were applied to all atoms distant from the NNRTI-binding site (defined as greater than 25 anstrom from the CA atom of residue 188) throughout the refinement.
RfactorNum. reflection% reflectionSelection details
Rfree0.287 1541 5 %RANDOM
Rwork0.205 ---
obs0.203 23338 89.2 %-
Refinement stepCycle: LAST / Resolution: 2.9→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7756 0 21 0 7777
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.4
Software
*PLUS
Name: CNS / Version: 1 / Classification: refinement
Refinement
*PLUS
Highest resolution: 2.9 Å / Lowest resolution: 30 Å / σ(F): 0 / % reflection Rfree: 5 %
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Type: c_angle_deg / Dev ideal: 1.4

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