Download HIV-1 Protease - Illinois State University

HIV-1 Protease
HIV-1 Protease is one of the targets in the therapeutic treatment of
AIDS. It cleaves the nascent polyproteins of HIV-1 and plays an
essential role in viral replication.
There are quite a few different inhibitors in existence for
HIV-1 Protease. Due to the rapid rate of viral replication and
the high error rate of reverse transcriptase result in HIV-1
mutants resistant to inhibitor action.
Peptide bond hydrolysis
Collectively, a total of 16 hydrogen bonds
were identified in the interaction
between HIV-1 protease and KNI-272. 9 of
the 16 hydrogen bonding interactions
were water mediated.
HIV-1 Protease enzyme molecule is a homodimer of two polypeptide chains each
containing 99 amino acid residues , and a single active site formed at the dimer
interface. The two monomers are covalently joined through a short linker.
Protein structure with MVT-101 inhibitor (shown in green)
Vertical view
Tiger Face!
Below is the KNI-272 inhibitor bonded to the active site of HIV-1 Protease. The main
interactions in the active site involve hydrogen bonding with four aspartates. Asp-25 is in
red, while Asp-29, Asp 125, and Asp 129 are green. Also shown are three water
molecules, HOH-301, HOH566, HOH608, which play a crucial role in bonding.
Interactions betwixt HIV-1 protease and its inhibitor should strongly depend on the
ionization state of the catalytic active site; KNI- 272 affinity to HIV-1 protease depends on
pH. At maximum affinity, only Asp-25 is protonated.
AD78
KB62
KB60
Darunavir
• two Asp-Thr-Gly catalytic triads (residue
numbers 25, 26, and 27 on one chain and 125,
126, and 127 on the second). The two Asp's
act as the main catalytic residues in the active
site and use a water molecule to help break
the protein chain that binds in the tunnel.
HIV-1 Protease
Inhibitor
Km (μM)
Vmax
(nmol/(min*mg)
Saquinavir
1.4
30.7
Nelfinavir
3.6
20.8
Indinavir
2.1
99.9
Amprenavir
46.9
96.4
Ritonavir
0.06
77.3
Saquinavir
1.19
93.6
Indinavir
0.47
112.2