View source for 4upj

[[Image:4upj.gif|left|200px]]

 {{Structure
|PDB= 4upj |SIZE=350|CAPTION= <scene name='initialview01'>4upj</scene>, resolution 1.9&Aring;
|SITE= 
|LIGAND= <scene name='pdbligand=U04:({3-[1-(4-HYDROXY-2-OXO-2H-CHROMEN-3-YL)-PROPYL]-PHENYLCARBAMOYL}-METHYL)-CARBAMIC+ACID+TERT-BUTYL+ESTER'>U04</scene>
|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/HIV-1_retropepsin HIV-1 retropepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.16 3.4.23.16] </span>
|GENE= 
|DOMAIN=
|RELATEDENTRY=
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4upj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4upj OCA], [http://www.ebi.ac.uk/pdbsum/4upj PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=4upj RCSB]</span>
}}

'''HUMAN IMMUNODEFICIENCY VIRUS TYPE 2 PROTEASE MUTANT WITH LYS 57 REPLACED BY LEU (K57L) COMPLEX WITH U097410 [4-HYDROXY-3-[1-[3-[[[[(TERT-BUTYLOXYCARBONYL) AMINOMETHYL]CARBONYL]AMINO]PHENYL]PROPYL]COUMARIN'''


==Overview==
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.

==About this Structure==
4UPJ is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_2 Human immunodeficiency virus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UPJ OCA]. 

==Reference==
Structure-based design of novel HIV protease inhibitors: carboxamide-containing 4-hydroxycoumarins and 4-hydroxy-2-pyrones as potent nonpeptidic inhibitors., Thaisrivongs S, Watenpaugh KD, Howe WJ, Tomich PK, Dolak LA, Chong KT, Tomich CC, Tomasselli AG, Turner SR, Strohbach JW, et al., J Med Chem. 1995 Sep 1;38(18):3624-37. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/7658450 7658450]
[[Category: HIV-1 retropepsin]]
[[Category: Human immunodeficiency virus 2]]
[[Category: Single protein]]
[[Category: Janakiraman, M N.]]
[[Category: Mulichak, A M.]]
[[Category: Watenpaugh, K D.]]
[[Category: hydrolase (acid protease)]]

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:40:32 2008''