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PDBsum entry 1upj

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Hydrolase (acid protease) PDB id
1upj
Jmol
Contents
Protein chain
99 a.a. *
Ligands
U01
Waters ×93
* Residue conservation analysis
PDB id:
1upj
Name: Hydrolase (acid protease)
Title: HIV-1 protease complex with u095438 [3-[1-(4-bromophenyl) is hydroxycoumarin
Structure: HIV-1 protease. Chain: a. Engineered: yes
Source: Human immunodeficiency virus 1. Organism_taxid: 11676. Strain: bh5. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Dimer (from PDB file)
Resolution:
2.22Å     R-factor:   0.193    
Authors: K.D.Watenpaugh,A.M.Mulichak,M.N.Janakiraman
Key ref: S.Thaisrivongs et al. (1995). Structure-based design of novel HIV protease inhibitors: carboxamide-containing 4-hydroxycoumarins and 4-hydroxy-2-pyrones as potent nonpeptidic inhibitors. J Med Chem, 38, 3624-3637. PubMed id: 7658450 DOI: 10.1021/jm00018a023
Date:
04-Mar-96     Release date:   14-Oct-96    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P03367  (POL_HV1BR) -  Gag-Pol polyprotein
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1447 a.a.
99 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 1: E.C.2.7.7.49  - RNA-directed Dna polymerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Deoxynucleoside triphosphate + DNA(n) = diphosphate + DNA(n+1)
Deoxynucleoside triphosphate
+ DNA(n)
= diphosphate
+ DNA(n+1)
   Enzyme class 2: E.C.2.7.7.7  - DNA-directed Dna polymerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Deoxynucleoside triphosphate + DNA(n) = diphosphate + DNA(n+1)
Deoxynucleoside triphosphate
+ DNA(n)
= diphosphate
+ DNA(n+1)
   Enzyme class 3: 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 4: E.C.3.1.26.13  - Retroviral ribonuclease H.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
   Enzyme class 5: 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
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     aspartic-type endopeptidase activity     1 term  

 

 
    reference    
 
 
DOI no: 10.1021/jm00018a023 J Med Chem 38:3624-3637 (1995)
PubMed id: 7658450  
 
 
Structure-based design of novel HIV protease inhibitors: carboxamide-containing 4-hydroxycoumarins and 4-hydroxy-2-pyrones as potent nonpeptidic inhibitors.
S.Thaisrivongs, K.D.Watenpaugh, W.J.Howe, P.K.Tomich, L.A.Dolak, K.T.Chong, C.C.Tomich, A.G.Tomasselli, S.R.Turner, J.W.Strohbach.
 
  ABSTRACT  
 
The low oral bioavailability and rapid biliary excretion of peptide-derived HIV protease inhibitors have limited their utility as potential therapeutic agents. Our broad screening program to discover nonpeptidic HIV protease inhibitors had previously identified compound II (phenprocoumon, K(i) = 1 muM) as a lead template. Crystal structures of HIV protease complexes containing the peptide-derived inhibitor I (1-(naphthoxyacetyl)-L-histidyl-5(S)-amino-6-cyclohexyl-3 (R),4(R)-dihydroxy-2(R)-isopropylhexanoyl-L-isoleucine N-(2-pyridylmethyl)amide) and nonpeptidic inhibitors, such as phenprocoumon (compound II), provided a rational basis for the structure-based design of more active analogues. This investigation reports on the important finding of a carboxamide functionally appropriately added to the 4-hydroxycoumarin and the 4-hydroxy-2-pyrone templates which resulted in a new promising series of nonpeptidic HIV protease inhibitors with improved enzyme-binding affinity. The most active diastereomer of the carboxamide-containing compound XXIV inhibited HIV-1 protease with a K(i) value of 0.0014 muM. This research provides a new design direction for the discovery of more potent HIV protease inhibitors as potential therapeutic agents for the treatment of HIV infection.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
17497016 I.Manolov, S.Raleva, P.Genova, A.Savov, L.Froloshka, D.Dundarova, and R.Argirova (2006).
Antihuman Immunodeficiency Virus Type 1 (HIV-1) Activity of Rare Earth Metal Complexes of 4-Hydroxycoumarins in Cell Culture.
  Bioinorg Chem Appl, (), 71938.  
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.  
15526325 M.Kontoyianni, G.S.Sokol, and L.M.McClellan (2005).
Evaluation of library ranking efficacy in virtual screening.
  J Comput Chem, 26, 11-22.  
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.  
12675950 E.Jenwitheesuk, and R.Samudrala (2003).
Improved prediction of HIV-1 protease-inhibitor binding energies by molecular dynamics simulations.
  BMC Struct Biol, 3, 2.  
11009599 M.J.Todd, I.Luque, A.Velázquez-Campoy, and E.Freire (2000).
Thermodynamic basis of resistance to HIV-1 protease inhibition: calorimetric analysis of the V82F/I84V active site resistant mutant.
  Biochemistry, 39, 11876-11883.  
10398408 M.Schapira, M.Totrov, and R.Abagyan (1999).
Prediction of the binding energy for small molecules, peptides and proteins.
  J Mol Recognit, 12, 177-190.  
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.  
9184138 J.S.Bardi, I.Luque, and E.Freire (1997).
Structure-based thermodynamic analysis of HIV-1 protease inhibitors.
  Biochemistry, 36, 6588-6596.  
8768903 H.J.Böhm (1996).
Current computational tools for de novo ligand design.
  Curr Opin Biotechnol, 7, 433-436.  
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.