1. HIV-1 PROTEASE Presented by: Aruni karunanyake 05-12-2006

2. AIDS VIRUS Human Immunodeficiency Virus Retrovirus. RNA--> DNA--> RNA--> Protein

4. Attachment of viron Binding to CD4 receptor Passage of viron content (RNA) Reverse transcription Reverse transcriptase DNA-RNA hybrid Degrade RNA (RnaseH) DNA Duplex Integration into host genome Transcription –Viral RNA Translation Immature viron HIV-1 protease Maturation of HIV virus

5. Function of HIV-1 Protease… Proteolytic enzyme HIV-1 Protease hydrolyzes viral polyproteins into functional protein products that are essential for viral assembly and subsequent activity

6. 2BPV (1999) 2BBB (2005) Resolution[Å]1.901.70 R-Value0.2060.217 R-Freen/a0.229

7. Structural Features.. Homodimer Identical conformation Each monomer 11Kd 99 Amino acid

8. Secondary structure.. 1 α-helix 5 β-sheets } anti parallel

9. The active site…. At the dimer interface 4 stranded β turn}Cleft Asp-Thr-Gly catalytic triad “ Aspartyle protease ” AA: 25-26-27

10. Mobile flaps-β hairpin loop “flexibility’ “mobility” Allows substrate to access to the active site …MIGGIGGFI..

11. Open Conformation Close conformation

12. Substrate Binding….

13. Proteolytic cleavage Water Molecule plays a major role “Loss of water results inactivation of PR” (Okimoto,et.al). General acid/base hydrolysis Activated by nucleophile & no acyle intermediate Different pKa values for Asp

14. Therapy for HIV ? Development of drug resistance by HIV High rate of Viral turnover Inability of HIV reverse transcripatse to correct transcriptional errors-enhance mutational errors Protease inhibitors as drugs