› 6voe

X-ray diffraction
1.3Å resolution

HIV-1 wild type protease with GRL-019-17A, a tricyclic cyclohexane fused tetrahydrofuranofuran (CHf-THF) derivative as the P2 ligand and a aminobenzothiazole(Abt)-based P2'-ligand

Released:
DOI: 10.2210/pdb6voe/pdb
PDB entry 6voe coloured by chain, front view.
PDB entry 6voe coloured by chain, side view.
PDB entry 6voe coloured by chain, top view.
Source organism: Human immunodeficiency virus 1
Primary publication:
Structure-Based Design of Highly Potent HIV-1 Protease Inhibitors Containing New Tricyclic Ring P2-Ligands: Design, Synthesis, Biological, and X-ray Structural Studies.
Ghosh AK, Kovela S, Osswald HL, Amano M, Aoki M, Agniswamy J, Wang YF, Weber IT, Mitsuya H
J Med Chem 63 4867-4879 (2020)
PMID: 32348139

Function and Biology Details

Reactions catalysed: 
Deoxynucleoside triphosphate + DNA(n) = diphosphate + DNA(n+1)
3'-end directed exonucleolytic cleavage of viral RNA-DNA hybrid
Endohydrolysis of RNA in RNA/DNA hybrids. Three different cleavage modes: 1. sequence-specific internal cleavage of RNA. Human immunodeficiency virus type 1 and Moloney murine leukemia virus enzymes prefer to cleave the RNA strand one nucleotide away from the RNA-DNA junction. 2. RNA 5'-end directed cleavage 13-19 nucleotides from the RNA end. 3. DNA 3'-end directed cleavage 15-20 nucleotides away from the primer terminus.
Specific for a P1 residue that is hydrophobic, and P1' variable, but often Pro.
Biochemical function:
Biological process:
Cellular component:
  • not assigned
Sequence domains:

Structure analysis Details

Assembly composition:
homo dimer (preferred)
Assembly name:
PDBe Complex ID:
PDB-CPX-136860 (preferred)
Entry contents:
1 distinct polypeptide molecule
Macromolecule:
Protease Chains: A, B
Molecule details ›
Chains: A, B
Length: 99 amino acids
Theoretical weight: 10.74 KDa
Source organism: Human immunodeficiency virus 1
Expression system: Escherichia coli BL21(DE3)
UniProt:
  • Canonical: P03367 (Residues: 501-599; Coverage: 7%)
Gene name: gag-pol
Sequence domains: Retroviral aspartyl protease

Ligands and Environments

4 bound ligands:
Ligand NA 1 x NA
Ligand CL 2 x CL
Ligand ACT 2 x ACT
Ligand T2R 1 x T2R
No modified residues

Experiments and Validation Details

Entry percentile scores
X-ray source: APS BEAMLINE 22-BM
Spacegroup: P21212
Unit cell:
a: 58.489Å b: 86.241Å c: 45.959Å
α: 90° β: 90° γ: 90°
R-values:
R R work R free
0.16 0.158 0.202
Expression system: Escherichia coli BL21(DE3)

Quick links

Citations

3 review citations

Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond.
Matthew et al. (2021)
2 more

1 mention without citation

Structure-Based Design of Highly Potent HIV-1 Protease Inhibitors Containing New Tricyclic Ring P2-Ligands: Design, Synthesis, Biological, and X-ray Structural Studies.
Ghosh et al. (2020)