066 protein structure as a target for ligand design
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066 protein structure as a target for ligand design
- 2. PROTEIN STRUCTURE AS A TARGET FOR LIGAND DESIGN
- 3. Finding the target Crystallography Pre-clinical trials, Clinical trials Protein structure Drug Development Diagram Synthesis and testing Available compound or lead compounds, substrates Protein structure Lead Improvement
- 4. Biological problem Target Structure of target (MMP9, Cellulase, Chymotrypsin) Proteins as a target
- 5. Matrix Metalloproteinase-9 - Zinc-dependent metalloproteinase - Degrades Extracellular matrix components Signal domain Fibronectin-like domain Propeptide Hinge region Hemopexin-like domain Zn2+ Catalytic domain 92 kD
- 6. - Physiological Conditions : - Tissue remodelling, wound healing, angiogenesis - Pathological Conditions : - Cancer metastasis, cardiovascular aneurysms and rupture MMP9 IMPORTANCE
- 8. Peter Carmeliet, (2000) J Clin Invest 105(11) 1519-1520 MMPs in cardiovascular aneurysms and rupture
- 9. Purification of truncated form of MMP-9 Expression in E. Coli Inclusion body Expression using Baculovirus system Zn2+ S P C F
- 10. Load Wash 0.1-2.0M NaCl Heparin-Sepharose column
- 12. Characterization of truncated form of MMP-9 - TIMP-1 binds and inhibits the catalytic domain - Fibronectin-like domain is not sufficient for heparin binding Zn2+ C F ~38kD Sadatmansoori, S (2001) protein expression and purification 23(3) 447-452.
- 13. The STRUCTURE OF CELLULASES FROM THE FUNGUS ASPERGILLUS NIGER
- 14. Problem : Cellulase producing fungi destroying cellulose-based materials. Target : Cellulase from Fungus Aspergillus niger. Cellulase as a Target
- 15. Ribbon Stereo Diagram of EglA
- 16. The Binding Cleft of EglA
- 18. Pd2+ Glu 116 Glu 204 Met 118
- 19. The STRUCTURE OF CELLULASES FROM A WOOD- EATING TERMITE
- 20. The problem: Termite - $1 billion damage a year! - 1000 lbs wood a year! - $15 million effort a year - Inhibition of digestive enzymes - The best choice is Cellulase.
- 21. NtEgl Crystals Initial crystals Final crystal
- 22. Ribbon Representation of NtEgl
- 23. Surface potential of NtEgl
- 24. W253 F205 D57 D54 W301 E412 Y408 W127 R361 H124 H359 Y417 Ca2+ W516 N-RE RE The Binding Cleft of NtEgl
- 25. D210 D213 E214 D254 N252 Water Water Ca2+ The Ca2+ Binding Site of NtEgl at pH 5.6
- 26. D213 E214 D210 D254 N252 The Ca2+ Binding Site of NtEgl at pH 2.5
- 27. H359 A55 Y417 Y408 Catalytic Acid/Base Glu 412 at pH 5.6 and 6.5
- 28. The STRUCTURE OF A SERINE PROTEASE FROM FIRE ANT
- 29. The Problem: fire ant
- 31. Asp 102 His 57 Ser 195 PMS
- 32. - C3 - Cymotrypsine - Trypsine - Elastase - Collagenase
- 33. 182 195 214 228 - Chymotrypsin CAG-ASGV-SSCMGDS … SWGSST-CS-TSTPGVY - Trypsin CVGFLEGGKDSCQGDS … SWGYG--CALPDNPGVY - Elastase CAGGDG-VRSGCQGDS … SFVSRLGCNVTRKPTVE - Collagenase CID-STGGKGTCDGDS … SFGAAAGCEA-GYPDAE - C3 CANDPSAQKGACKGDS … SW--SLDCALTTHPTVY Asp 102 His 57 Ser 195PMS Ser 217
- 34. Asp 102 His 57 Ser 195 PMS IPS
- 36. Structure-Based Drug Design Protein structure Small molecule database Docking Protein structure Crystallography Molecular Mechanics Dynamics calculations Protein structure
- 37. Touching Molecules: force feedback as an aid to docking
- 38. Acknowledgement -Dr. Edgar Meyer - Dr. Linda A. Guarino - Dr. Hirofumi Watanabe - Dr. Arnold Wartenberg - Dr. Sepideh Sadatmansoori - Dr. Reza Forough - Dr. Erik Meyer - Dr. Stanley and Rosemarie Swanson - Robert A. Welch Foundation - Texas Advanced Technology Program