3DJK

Wild Type HIV-1 Protease with potent Antiviral inhibitor GRL-0255A

Summary for 3DJK

• Entry DOI: 10.2210/pdb3djk/pdb
• Related: 2HB3 2IEN 2Z4O 3DK1
• Descriptor: Protease, SODIUM ION, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: hiv-1, wild type protease, protease inhibitor, hydrolase, aids, aspartyl protease, capsid maturation, capsid protein, cytoplasm, dna integration, dna recombination, dna-directed dna polymerase, endonuclease, lipoprotein, magnesium, metal-binding, multifunctional enzyme, myristate, nuclease, nucleotidyltransferase, nucleus, phosphoprotein, protease, ribosomal frameshifting, rna-binding, rna-directed dna polymerase, transferase, viral nucleoprotein, virion, zinc, zinc-finger
• Biological source: Human immunodeficiency virus type 1 (HIV-1)
• Cellular location: Gag-Pol polyprotein: Host cell membrane ; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03367
• Total number of polymer chains: 2
• Total formula weight: 22184.36

Authors

Wang, Y.F.,Weber, I.T. (deposition date: 2008-06-23, release date: 2008-09-30, Last modification date: 2023-11-01)

Primary citation

Ghosh, A.K.,Gemma, S.,Baldridge, A.,Wang, Y.F.,Kovalevsky, A.Y.,Koh, Y.,Weber, I.T.,Mitsuya, H.
Flexible cyclic ethers/polyethers as novel P2-ligands for HIV-1 protease inhibitors: design, synthesis, biological evaluation, and protein-ligand X-ray studies
J.Med.Chem., 51:6021-6033, 2008

PubMed Abstract: We report the design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors. The inhibitors incorporate stereochemically defined flexible cyclic ethers/polyethers as high affinity P2-ligands. Inhibitors containing small ring 1,3-dioxacycloalkanes have shown potent enzyme inhibitory and antiviral activity. Inhibitors 3d and 3h are the most active inhibitors. Inhibitor 3d maintains excellent potency against a variety of multi-PI-resistant clinical strains. Our structure-activity studies indicate that the ring size, stereochemistry, and position of oxygens are important for the observed activity. Optically active synthesis of 1,3-dioxepan-5-ol along with the syntheses of various cyclic ether and polyether ligands have been described. A protein-ligand X-ray crystal structure of 3d-bound HIV-1 protease was determined. The structure revealed that the P2-ligand makes extensive interactions including hydrogen bonding with the protease backbone in the S2-site. In addition, the P2-ligand in 3d forms a unique water-mediated interaction with the NH of Gly-48.

PubMed: 18783203
DOI: 10.1021/jm8004543

Experimental method

X-RAY DIFFRACTION (1 Å)