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PDBsum entry 1d4s
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Hydrolase PDB id
1d4s

 

 

 

 

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Contents
Protein chains
99 a.a. *
Ligands
TPV
Waters ×133
* Residue conservation analysis
PDB id:
1d4s
Name: Hydrolase
Title: HIV-1 protease v82f/i84v double mutant/tipranavir complex
Structure: Protein (HIV-1 protease). Chain: a, b. Synonym: human immunodeficiency virus type 1 protease. Engineered: yes. Mutation: yes
Source: Human immunodeficiency virus 1. Organism_taxid: 11676. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Dimer (from PQS)
Resolution:
2.50Å     R-factor:   0.179     R-free:   0.294
Authors: K.D.Watenpaugh,M.N.Janakiraman
Key ref: S.Thaisrivongs et al. (1996). Structure-based design of HIV protease inhibitors: sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrones as non-peptidic inhibitors. J Med Chem, 39, 4349-4353. PubMed id: 8893827 DOI: 10.1021/jm960541s
Date:
05-Oct-99     Release date:   12-Oct-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P03367  (POL_HV1BR) -  Gag-Pol polyprotein from Human immunodeficiency virus type 1 group M subtype B (isolate BRU/LAI)
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1447 a.a.
99 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class 1: E.C.2.7.7.-  - ?????
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 2: E.C.2.7.7.49  - RNA-directed Dna polymerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
DNA(n)
 + 2'-deoxyribonucleoside 5'-triphosphate
 = DNA(n+1)
 + diphosphate
   Enzyme class 3: E.C.2.7.7.7  - DNA-directed Dna polymerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + diphosphate
DNA(n)
 + 2'-deoxyribonucleoside 5'-triphosphate
 = DNA(n+1)
 + diphosphate
   Enzyme class 4: E.C.3.1.-.-
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 5: E.C.3.1.13.2  - exoribonuclease H.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Exonucleolytic cleavage to 5'-phosphomonoester oligonucleotides in both 5'- to 3'- and 3'- to 5'-directions.
   Enzyme class 6: E.C.3.1.26.13  - retroviral ribonuclease H.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 7: E.C.3.4.23.16  - HIV-1 retropepsin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Specific for a P1 residue that is hydrophobic, and P1' variable, but often Pro.
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1021/jm960541s J Med Chem 39:4349-4353 (1996)
PubMed id: 8893827  
 
 
Structure-based design of HIV protease inhibitors: sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrones as non-peptidic inhibitors.
S.Thaisrivongs, H.I.Skulnick, S.R.Turner, J.W.Strohbach, R.A.Tommasi, P.D.Johnson, P.A.Aristoff, T.M.Judge, R.B.Gammill, J.K.Morris, K.R.Romines, R.A.Chrusciel, R.R.Hinshaw, K.T.Chong, W.G.Tarpley, S.M.Poppe, D.E.Slade, J.C.Lynn, M.M.Horng, P.K.Tomich, E.P.Seest, L.A.Dolak, W.J.Howe, G.M.Howard, K.D.Watenpaugh.
 
  ABSTRACT  
 
No abstract given.

 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19928916 D.Das, Y.Koh, Y.Tojo, A.K.Ghosh, and H.Mitsuya (2009).
Prediction of potency of protease inhibitors using free energy simulations with polarizable quantum mechanics-based ligand charges and a hybrid water model.
  J Chem Inf Model, 49, 2851-2862.  
19254207 P.M.Colman (2009).
New antivirals and drug resistance.
  Annu Rev Biochem, 78, 95.  
18004760 T.Hou, W.A.McLaughlin, and W.Wang (2008).
Evaluating the potency of HIV-1 protease drugs to combat resistance.
  Proteins, 71, 1163-1174.  
18384529 W.Sherman, and B.Tidor (2008).
Novel method for probing the specificity binding profile of ligands: applications to HIV protease.
  Chem Biol Drug Des, 71, 387-407.  
17635930 Y.Koh, S.Matsumi, D.Das, M.Amano, D.A.Davis, J.Li, S.Leschenko, A.Baldridge, T.Shioda, R.Yarchoan, A.K.Ghosh, and H.Mitsuya (2007).
Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization.
  J Biol Chem, 282, 28709-28720.  
17712762 Z.Temesgen, and J.Feinberg (2007).
Tipranavir: a new option for the treatment of drug-resistant HIV infection.
  Clin Infect Dis, 45, 761-769.  
16508951 A.L.Perryman, J.H.Lin, and J.A.McCammon (2006).
Restrained molecular dynamics simulations of HIV-1 protease: the first step in validating a new target for drug design.
  Biopolymers, 82, 272-284.  
16784458 A.L.Perryman, J.H.Lin, and J.Andrew McCammon (2006).
Optimization and computational evaluation of a series of potential active site inhibitors of the V82F/I84V drug-resistant mutant of HIV-1 protease: an application of the relaxed complex method of structure-based drug design.
  Chem Biol Drug Des, 67, 336-345.  
16928764 J.D.Baxter, J.M.Schapiro, C.A.Boucher, V.M.Kohlbrenner, D.B.Hall, J.R.Scherer, and D.L.Mayers (2006).
Genotypic changes in human immunodeficiency virus type 1 protease associated with reduced susceptibility and virologic response to the protease inhibitor tipranavir.
  J Virol, 80, 10794-10801.  
16492163 P.Bandyopadhyay, and B.R.Meher (2006).
Drug resistance of HIV-1 protease against JE-2147: I47V mutation investigated by molecular dynamics simulation.
  Chem Biol Drug Des, 67, 155-161.  
16010346 G.P.McGlacken, and I.J.Fairlamb (2005).
2-Pyrone natural products and mimetics: isolation, characterisation and biological activity.
  Nat Prod Rep, 22, 369-385.  
15757454 V.R.Kandula, H.Khanlou, and C.Farthing (2005).
Tipranavir: a novel second-generation nonpeptidic protease inhibitor.
  Expert Rev Anti Infect Ther, 3, 9.  
15044738 A.L.Perryman, J.H.Lin, and J.A.McCammon (2004).
HIV-1 protease molecular dynamics of a wild-type and of the V82F/I84V mutant: possible contributions to drug resistance and a potential new target site for drugs.
  Protein Sci, 13, 1108-1123.  
15097154 S.McCallister, H.Valdez, K.Curry, T.MacGregor, M.Borin, W.Freimuth, Y.Wang, and D.L.Mayers (2004).
A 14-day dose-response study of the efficacy, safety, and pharmacokinetics of the nonpeptidic protease inhibitor tipranavir in treatment-naive HIV-1-infected patients.
  J Acquir Immune Defic Syndr, 35, 376-382.  
14562864 P.Yeni (2003).
Tipranavir: a protease inhibitor from a new class with distinct antiviral activity.
  J Acquir Immune Defic Syndr, 34, S91-S94.  
14585057 S.Mehandru, and M.Markowitz (2003).
Tipranavir: a novel non-peptidic protease inhibitor for the treatment of HIV infection.
  Expert Opin Investig Drugs, 12, 1821-1828.  
10997398 B.A.Larder, K.Hertogs, S.Bloor, C.H.van den Eynde, W.DeCian, Y.Wang, W.W.Freimuth, and G.Tarpley (2000).
Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples.
  AIDS, 14, 1943-1948.  
10468550 I.D.Kuntz, K.Chen, K.A.Sharp, and P.A.Kollman (1999).
The maximal affinity of ligands.
  Proc Natl Acad Sci U S A, 96, 9997.  
10380352 S.Thaisrivongs, and J.W.Strohbach (1999).
Structure-based discovery of Tipranavir disodium (PNU-140690E): a potent, orally bioavailable, nonpeptidic HIV protease inhibitor.
  Biopolymers, 51, 51-58.  
10506434 Z.Zhao, K.A.Koeplinger, and D.J.Waldon (1999).
Stereoselective hydroxylation of nonpeptidic HIV protease inhibitors by CYP2D6.
  Chirality, 11, 731-739.  
9754946 A.Molla, G.R.Granneman, E.Sun, and D.J.Kempf (1998).
Recent developments in HIV protease inhibitor therapy.
  Antiviral Res, 39, 1.  
  9371335 K.T.Chong, and P.J.Pagano (1997).
In vitro combination of PNU-140690, a human immunodeficiency virus type 1 protease inhibitor, with ritonavir against ritonavir-sensitive and -resistant clinical isolates.
  Antimicrob Agents Chemother, 41, 2367-2373.  
  9145869 S.M.Poppe, D.E.Slade, K.T.Chong, R.R.Hinshaw, P.J.Pagano, M.Markowitz, D.D.Ho, H.Mo, R.R.Gorman, T.J.Dueweke, S.Thaisrivongs, and W.G.Tarpley (1997).
Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor.
  Antimicrob Agents Chemother, 41, 1058-1063.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.

 

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