proteins with complex architecture as potential targets for drug design: a case study of...
TRANSCRIPT
![Page 1: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/1.jpg)
Raunak Shrestha
Source: Mészáros B, Tóth J, Vértessy BG, Dosztányi Z, Simon I. Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis. PLoS Comput Biol. 2011 Jul;7(7):e1002118.
29th September 2011
![Page 2: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/2.jpg)
A brief overview
• Tuberculosis (TB) – a high burden disease
• Causative agent – Mycobacterium tuberculosis (MTB)
• TB: Ancient disease
• co-habitation of MTB and humans : ~ 9000 years
• 1950s – 1970s : Massive use of Antibiotics
• 1980s – significant reduction in TB
• 1990s : Re-emergence of TB cases • Multi Drug-Resistant TB (MDR-TB)
• Extensively Drug-Resistant TB (XDR-TB)
• STRONG NEED OF NEW DRUG TARGETS AGAINST MTB
![Page 3: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/3.jpg)
Evolutionary Approach in Drug Target Screening
Human Proteins
Human Micro-floras/Eukaryotes
Mycobacteria
Tuberculous Non - Tuberculous
MTB Other MTB-complex Mycobacteria
![Page 4: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/4.jpg)
Comparative sequence analysis of the MTB proteome
![Page 5: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/5.jpg)
Domain composition
• Domains: evolutionary building blocks of proteins
• Pfam database (http://pfam.sanger.ac.uk/) used to determine domain composition in MTB• 3948 MTB proteins had 2099 different domains
• Proteome dataset:• 1,904,578 protein sequences from 467 (20 eukaryotic including
human and 447 bacterial) known complete proteomes
• PSI-BLAST to search for sequence similarities of the domains in MTB proteome with the Proteome dataset from 467 organisms.• Significant hits : E-values < 10E-4
![Page 6: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/6.jpg)
Domain composition
Figure : Occurrences of domains of M. tuberculosis in other organisms.
Pfam domains only cover about 63% of all
residues
![Page 7: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/7.jpg)
Complex Domain Architecture
Domain 1 Domain 2
Disordered regions : domain linkers
disorder-to-order transition
Other protein or molecule
Disordered protein : high free energy
Ordered protein : stable conformation
![Page 8: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/8.jpg)
Disordered Proteins
• IUPred (http://iupred.enzim.hu/): prediction of protein disorder
• Scores between 0 to 1 for every amino-acid residues for its tendency towards disorderness
• >= 0.5 : more disordered
• < less disordered
• Disordered proteins have distinct sequence properties
• ANCHOR (http://anchor.enzim.hu/): recognizes specific sequence properties of the disordered proteins that can undergo disorder-to-order transition
• Compositional Bias
• Low complexity regions
![Page 9: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/9.jpg)
Disordered Proteins
• 11.8 % residues – disordered segments
• 5.7% residues - disordered binding region
• Relatively high values for the disordered proteins as compared to most bacteria
• 7.2% residues in disordered protein overlap with Annotated Pfam domains
• 28% of the protein residues in MTB not covered by Pfam or by disordered and disordered binding regions
• MTB specific proteins?
• Limitations of current methods !!!
![Page 10: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/10.jpg)
Categorization of MTB proteins based on their specificity and function.
• large-scale sequence similarity search for all proteins in MTB with wide-range of proteins from other organism
• Categorization of proteins at various evolutionary levels
• Proteins specific to MTB or highly similar with M. bovis
• Proteins at the level of Mycobacteria
• Proteins found in other bacteria
• Proteins that are ubiquitous from mycobacteria to eukaryotes
• Functional grouping of proteins
• TubercuList (http://genolist.pasteur.fr/TubercuList/)
![Page 11: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/11.jpg)
Categorization of MTB proteins based on their specificity and function.
1. virulence, detoxification, adaptation2. lipid metabolism3. Information pathways4. cell wall and cell processes5. insertion sequences and phages;
6. PE/PPE7. intermediary metabolism and respiration8. regulatory proteins9. conserved hypotheticals
![Page 12: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/12.jpg)
Similarity based clustering of MTB proteins• enrichment and
depletion of protein segments in the MTB proteome across different species.
Figure: Clusters of MTB proteins based on local protein similarities. Hierarchical tree representing the clustering of the 3,948 MTB proteins
![Page 13: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/13.jpg)
Similarity based clustering of MTB proteins
![Page 14: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/14.jpg)
Similarity based clustering of MTB proteins
![Page 15: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/15.jpg)
Similarity based clustering of MTB proteins
![Page 16: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/16.jpg)
pkn family
![Page 17: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/17.jpg)
PE/PPE family
![Page 18: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/18.jpg)
Conclusion
• pkn and PE/PPE, that showed unusual species-specific enrichment of domains
• Probable candidate for future deeper level drug target screening and drug design
![Page 19: Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis](https://reader035.vdocument.in/reader035/viewer/2022081401/55957e701a28abf6028b4708/html5/thumbnails/19.jpg)
Limitations
• Inclusion of only MTB-H37Rv strain (well characterized)
• Failure to include other strains like “Beijing Genotype” which is widely reported MTB genotype strain