066 protein structure as a target for ligand design
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1) The document discusses using protein structures as targets for ligand design in drug development. It provides examples of targeting matrix metalloproteinase 9 (MMP9), cellulases, and a serine protease from fire ants. 2) Specific protein structures that are discussed include truncated forms of MMP9, cellulases from Aspergillus niger and a wood-eating termite, and a C3 serine protease from fire ants. Crystallization and characterization methods are described. 3) The structures provide insight into binding sites and catalytic domains that can be targeted by small molecule ligands during structure-based drug design to develop inhibitors for conditions like cancer metastasis and termite damage.
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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