4e43 | pdb_00004e43

HIV protease (PR) dimer with acetate in exo site and peptide in active site

spinqualitylabelsall models 4e43, resolution 1.54Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4e43 is a 3 chain structure with sequence from Human immunodeficiency virus 1 and Unidentified. This structure supersedes the now removed PDB entry 3kf1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACT, BME, DMS, GOL Related: 3kf1 Gene: POL (Human immunodeficiency virus 1) Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed We have employed a fragment-based screen against wild-type (NL4-3) HIV protease (PR) using the Active Sight fragment library and X-ray crystallography. The experiments reveal two new binding sites for small molecules. PR was co-crystallized with fragments, or crystals were soaked in fragment solutions, using five crystal forms, and 378 data sets were collected to 2.3-1.3 A resolution. Fragment binding induces a distinct conformation and specific crystal form of TL-3 inhibited PR during co-crystallization. One fragment, 2-methylcyclohexanol, binds in the 'exo site' adjacent to the Gly(16)Gly(17)Gln(18)loop where the amide of Gly(17)is a specific hydrogen bond donor, and hydrophobic contacts occur with the side chains of Lys(14)and Leu(63). Another fragment, indole-6-carboxylic acid, binds on the 'outside/top of the flap' via hydrophobic contacts with Trp(42), Pro(44), Met(46), and Lys(55), a hydrogen bond with Val(56), and a salt-bridge with Arg(57). 2-acetyl-benzothiophene also binds at this site. This study is the first fragment-based crystallographic screen against HIV PR, and the first time that fragments were screened against an inhibitor-bound drug target to search for compounds that both bind to novel sites and stabilize the inhibited conformation of the target. Fragment-based screen against HIV protease.,Perryman AL, Zhang Q, Soutter HH, Rosenfeld R, McRee DE, Olson AJ, Elder JE, Stout CD Chem Biol Drug Des. 2010 Mar;75(3):257-68. Epub 2010 Jan 19. PMID:20659109 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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