3KFP

HIV Protease (PR) with inhibitor TL-3 bound, and DMSOs in exo site

Summary for 3KFP

• Entry DOI: 10.2210/pdb3kfp/pdb
• Related: 2AZ8 3KF0 3KF1 3KFN 3KFR 3KFS
• Related PRD ID: PRD_000434
• Descriptor: Protease, benzyl [(1S,4S,7S,8R,9R,10S,13S,16S)-7,10-dibenzyl-8,9-dihydroxy-1,16-dimethyl-4,13-bis(1-methylethyl)-2,5,12,15,18-pentaoxo-20-phenyl-19-oxa-3,6,11,14,17-pentaazaicos-1-yl]carbamate, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: hiv-1, protease, exo site, aspartyl protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 1
• Total formula weight: 12053.44

Authors

Stout, C.D. (deposition date: 2009-10-27, release date: 2010-02-23, Last modification date: 2023-09-06)

Primary citation

Perryman, A.L.,Zhang, Q.,Soutter, H.H.,Rosenfeld, R.,McRee, D.E.,Olson, A.J.,Elder, J.E.,David Stout, C.
Fragment-based screen against HIV protease.
Chem.Biol.Drug Des., 75:257-268, 2010

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: 20659109
DOI: 10.1111/j.1747-0285.2009.00943.x

Experimental method

X-RAY DIFFRACTION (1.77 Å)