ucsd deans and chairs presentation - pdb & drug discovery
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The RCSB Protein Data Bank
www.rcsb.org
Phil BourneSSPPS
pbourne@ucsd.edu
1/25/11 UCSD Deans and Chairs Meeting
Agenda
What is the RCSB PDB and what does it bring to SSPPS/UCSD?
Examples of how it is being used in drug discovery
How SSPPS/UCSD might leverage it going forward
1/25/11 UCSD Deans and Chairs Meeting
What is the Protein Data Bank (PDB)?
The single community owned worldwide repository on the structures of publically accessible biological macromolecules
A resource used by ~ 200,000 individuals per month
A resource distributing equivalent to ¼ the National Library of Congress each month
1/25/11 UCSD Deans and Chairs Meeting
Nu
mb
er o
f re
leas
ed e
ntr
ies
Year
Total Contents by Year
1/25/11
Depositor locations
Download locations
RCSB PDB
PDBe
PDBj
Depositions since 2000
1/25/11 UCSD Deans and Chairs Meeting
Cooperative Community Action
Individual letters to editors of journals
Committees IUCr commission on
Biological Macromolecules ACA/USNCCr Richards committee
Funding agencies Articles in journals
Marvin Cassman Fred Richards Richard Dickerson
1/25/11 UCSD Deans and Chairs Meeting
46157
1301
1093
755
39
582655
Structure distribution
Other
Protein only
Protein-DNA complexes
DNA only
Protein-RNA complexesRNA only
RNA-DNA hybrid
Resolution distribution:
protein structures
Resolution distribution:
other structures
Year
Res
olu
tion
Resolution distribution: all structures
Structure determination
methods
Num
ber
of
stru
ctu
res
Year
What has the PDB enabled?
Safe storage and retrieval of macromolecular structure data
Increased understanding of sequence-structure-function relationships:
– A “parts list” for structure modeling and prediction– Structure based drug design– Protein structure classification– The details in large scale interactions
1/25/11 UCSD Deans and Chairs Meeting
Lysozyme: Lessons learned
Blake, Koenig, Mair, North, Phillips, Sarma (1965) Nature 206: 757.
T4 bacteriophage (459 structures) Amino acid replacement studies
suggest that fraction of amino acid residues that define the structure of T4 lysozyme is about 50% B.W. Matthews (1996) FASEB J.10: 35-41.
Insight into folding and catalysis
Hen egg white (297 structures) Low sequence identity Structural similarity of active site
to T4B.W. Matthews, M.G. Remington, M.G. Grutter, W.F. Anderson (1981) J.Mol.Biol. 147: 545-58.
Insight into evolution and catalysis1/25/11 UCSD Deans and Chairs Meeting
Myoglobin and hemoglobin: Lessons learned
Lodish et al.6
Whale myoglobin (185 structures) Different ligands: oxygen, carbon dioxide1
Amino acid substitution studies2
Laue studies3
Insight into function and dynamics
Other species myoglobin Low sequence identity, same structure4
Insight into evolution
Human hemoglobin (178 structures)
Insight into function and disease (sickle cell anemia, thalassemia)5
Other species hemoglobin Low sequence identity, same structure4
Profound insight into evolution1Kuriyan, Wilz, Karplus, Petsko (1986) J. Mol. Biol. 192:133–154; 2Quillin, Arduini, Olson, Phillips, Jr. (1993) J. Mol. Biol. 234: 140–155, Carver, Brantley Jr, Singleton, Arduini, Quillin, Phillips Jr, Olson (1992) J. Biol. Chem. 267:14443–14450; 3Bourgeois, Vallone, Schotte, Arcovito, Miele, Sciara, Wulff, Anfinrud, Brunori (2003) PNAS 100: 8704-8709; 4Dickerson, Geis (1983) Hemoglobin: structure, function, and pathology; 5Kidd, Baker, Mathews, Brittain Baker (2001) Prot. Sci. 10:1739-1749, Harrington, Adachi, Royer Jr. (1998) J. Biol. Chem. 273: 32690 - 32696; 6Lodish, Berk, Zipursky, Matsudaira, Balitmore, Darnell (2000) Molecular Cell Biology WH Freeman & Co.
Agenda
What is the PDB and what does it bring to UCSD?
Examples of how it is being used in drug discovery
How UCSD might leverage it going forward
1/25/11 UCSD Deans and Chairs Meeting
RCSB PDB Pharmacology/Drug View
Establish linkages to drug resources (FDA, PubChem, DrugBank, ChEBI, BindingDB etc.)
Create query capabilities for drug information
Provide superposed views of ligand binding sites
Analyze and display protein-ligand interactions
Drug Name Asp
Aspirin
Has Bound Drug% Similarity to Drug Molecule 100
Mockups of drug view features
HIV-related structures
311
110
39
27
122
Year
Protease
Reverse Transcriptase
Gag protein
Integrase
Other
HIV-1 reverse transcriptase
Amprenavir (GSK) Fosamprenavir (GSK)
Lopinavir (Abbott) Atazanavir (BMS)
Nelfinavir (Agouron) Darunavir (Tibotec)
Tipranavir (BI) Indinavir (Merck)
Ritonavir (Abbott) Saquinavir (Roche)
2R5P, 2B7Z, 2AVV, 2AVO, 2AVS, 1SGU, 1SDT, 1SDV, 1SDU, 1K6C, 1C6Y, 2BPX, 1HSG, 1HSH
1T7J, 1HPV
2B60, 1RL8, 1SH9, 1N49, 1HXW
2QAK, 2PYM, 2Q63, 2PYN, 2Q64, 2R5Q, 1OHR
2O4N, 2O4L, 2O4P, 1D4Y, 1D4S
3D1X, 3D1Y, 3CYX, 2NMW, 2NMZ, 2NNP, 2NMY, 2NNK, 1C6Z, 1FB7
2FXE, 2FXD, 2O4K, 2AQU, 2FND 2RKG, 2RKF,
2QHC, 2Z54, 2Q5K, 2O4S, 1RV7, 1MUI
Abacavir (GSK)
Nevirapine (BI) Stavudin (BMS)
Efavirenz (BMS) Lamivudine (GSK)
Zidovudine (GSK) Emtricitabine (Gilead)
Tenofovir (Gilead) Zalcitabine (Hoffmann- LaRoche)
Etravirine (Tibotec) Delavirdine (Pfizer)
2HND, 2HNY, 1S1U, 1S1X, 1LW0, 1LWE, 1LWC, 1LWF, 1JLB, 1JLF, 1FKP, 1VRT, 3HVT
1JKH, 1IKW, 1IKV, 1FKO, 1FK9
1S6P
1T05
HIV-1 protease
1/25/11
Worldwide Protein Data Bank
www.wwpdb.org
Consider one example of using the corpus as a whole from our own research – high throughput hypothesis generation for use in drug discovery
1/25/11 UCSD Deans and Chairs Meeting
Polypharmacology - One Drug Binds to Multiple Targets
• Tykerb – Breast cancer
• Gleevac – Leukemia, GI cancers
• Nexavar – Kidney and liver cancer
• Staurosporine – natural product – alkaloid – uses many e.g., antifungal antihypertensive
Collins and Workman 2006 Nature Chemical Biology 2 689-700
The TB-Drugome
1. Determine the TB structural proteome
2. Determine all known drug binding sites from the PDB
3. Determine which of the sites found in 2 exist in 1
4. Call the result the TB-drugome
Kinnings et al 2010 PLoS Comp Biol 6(11): e1000976
UCSD Deans and Chairs Meeting
1. Determine the TB Structural Proteome
284
1, 446
3, 996 2, 266
TB proteome
homology
models
solve
d
structu
res
High quality homology models from ModBase (http://modbase.compbio.ucsf.edu) increase structural coverage from 7.1% to 43.3%
1/25/11 UCSD Deans and Chairs Meeting
2. Determine all Known Drug Binding Sites in the PDB
Searched the PDB for protein crystal structures bound with FDA-approved drugs
268 drugs bound in a total of 931 binding sites
No. of drug binding sites
MethotrexateChenodiol
AlitretinoinConjugated estrogens
DarunavirAcarbose
1/25/11 UCSD Deans and Chairs Meeting
Map 2 onto 1 – The TB-Drugomehttp://funsite.sdsc.edu/drugome/TB/
Similarities between the binding sites of M.tb proteins (blue), and binding sites containing approved drugs (red).
From a Drug Repositioning Perspective
Similarities between drug binding sites and TB proteins are found for 61/268 drugs
41 of these drugs could potentially inhibit more than one TB protein
No. of potential TB targets
raloxifenealitretinoin
conjugated estrogens &methotrexate
ritonavir
testosteronelevothyroxine
chenodiol
1/25/11
Top 5 Most Highly Connected Drugs
Drug Intended targets Indications No. of connections TB proteins
levothyroxine transthyretin, thyroid hormone receptor α & β-1, thyroxine-binding globulin, mu-crystallin homolog, serum albumin
hypothyroidism, goiter, chronic lymphocytic thyroiditis, myxedema coma, stupor
14
adenylyl cyclase, argR, bioD, CRP/FNR trans. reg., ethR, glbN, glbO, kasB, lrpA, nusA, prrA, secA1, thyX, trans. reg. protein
alitretinoin retinoic acid receptor RXR-α, β & γ, retinoic acid receptor α, β & γ-1&2, cellular retinoic acid-binding protein 1&2
cutaneous lesions in patients with Kaposi's sarcoma 13
adenylyl cyclase, aroG, bioD, bpoC, CRP/FNR trans. reg., cyp125, embR, glbN, inhA, lppX, nusA, pknE, purN
conjugated estrogens estrogen receptor
menopausal vasomotor symptoms, osteoporosis, hypoestrogenism, primary ovarian failure
10
acetylglutamate kinase, adenylyl cyclase, bphD, CRP/FNR trans. reg., cyp121, cysM, inhA, mscL, pknB, sigC
methotrexatedihydrofolate reductase, serum albumin
gestational choriocarcinoma, chorioadenoma destruens, hydatidiform mole, severe psoriasis, rheumatoid arthritis
10
acetylglutamate kinase, aroF, cmaA2, CRP/FNR trans. reg., cyp121, cyp51, lpd, mmaA4, panC, usp
raloxifeneestrogen receptor, estrogen receptor β
osteoporosis in post-menopausal women 9
adenylyl cyclase, CRP/FNR trans. reg., deoD, inhA, pknB, pknE, Rv1347c, secA1, sigC
Agenda
What is the PDB and what does it bring to UCSD?
Examples of how it is being used in drug discovery
How UCSD might leverage it going forward
1/25/11 UCSD Deans and Chairs Meeting
How UCSD Might Leverage the PDB
Part of the foundation of a drug discovery effort.
Outreach tool The Devil is in the Details - talented group of
PDB scientists capable of working with the details
Lots of experience with UCSD’s unique infrastructure, data curation, management, dissemination etc. available for new initiatives
1/25/11 UCSD Deans and Chairs Meeting
Acknowledgements
Funding Agencies: NSF, NIGMS, DOE, NLM, NCI, NCRR, NIBIB, NINDS, NIDDK
241/25/11 UCSD Deans and Chairs Meeting
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