Summary for 4E43
| Entry DOI | 10.2210/pdb4e43/pdb |
| Related | 3KF1 |
| Descriptor | Protease, Random peptide, DIMETHYL SULFOXIDE, ... (7 entities in total) |
| Functional Keywords | hiv-1 protease, exo site, aspartyl protease, fragment screen, hydrolase |
| Biological source | Human immunodeficiency virus 1 More |
| Total number of polymer chains | 3 |
| Total formula weight | 23779.24 |
| Authors | Stout, C.D. (deposition date: 2012-03-11, release date: 2012-05-30, Last modification date: 2024-02-28) |
| Primary citation | Perryman, A.L.,Zhang, Q.,Soutter, H.H.,Rosenfeld, R.,McRee, D.E.,Olson, A.J.,Elder, J.E.,Stout, C.D. Fragment-based screen against HIV protease. Chem.Biol.Drug Des., 75:257-268, 2010 Cited by PubMed Abstract: 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. PubMed: 20659109DOI: 10.1111/j.1747-0285.2009.00943.x PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.54 Å) |
Structure validation
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