Modeling the Structures of Proteins and Macromolecular Assemblies Depts. Of Biopharmaceutical Sciences and Pharmaceutical Chemistry California Institute for Quantitative Biomedical Research University of California at San Francisco Andrej Šali http:// salilab.org/ 3/25/03
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Modeling the Structures of Proteins and Macromolecular Assemblies Depts. Of Biopharmaceutical Sciences and Pharmaceutical Chemistry California Institute.
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Modeling the Structures of Proteins andMacromolecular Assemblies
Depts. Of Biopharmaceutical Sciences and Pharmaceutical ChemistryCalifornia Institute for Quantitative Biomedical Research
University of California at San Francisco
Andrej Šali
http://salilab.org/
3/25/03
1. Yeast and E. coli ribosomes: Electron microscopy, comparative modeling, and structural genomics.
2. Yeast Nuclear Pore Complex: Low-resolution modeling of large assemblies; bridging the gaps between structural biology, proteomics, and system biology.
3. Comments.
4/6/03
S. cerevisiae ribosome
C. Spahn, R. Beckmann, N. Eswar, P. Penczek, A. Sali, G. Blobel, J. Frank. Cell 107, 361-372, 2001.
Fitting of comparative models into 15Å cryo- electron density map.
43 proteins could be modeled on 20-56% seq.id. to a known structure.
The modeled fraction of the proteins ranges from 34-99%.
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E. coli ribosomeH.Gao, J.Sengupta, M.Valle, A. Korostelev, N.Eswar, S.Stagg, P.Van Roey, R.Agrawal, S.Harvey, A.Sali, M.Chapman, and J.Frank. Cell, in press.
Upon EF-G binding, the
ribosome becomes less
compact. In contrast to
mRNA, many protein
contacts undergo large
conformational changes,
suggesting ribosomal
proteins facilitate the
dynamics of translation.
4/6/03
STARTSTART
Get profile for sequence (NR)Get profile for sequence (NR)
Scan sequence profile against representative PDB chains
Scan sequence profile against representative PDB chains
Scan PDB chain profiles against sequence
Scan PDB chain profiles against sequence
PS
I-B
LA
ST
MODPIPE: Large-Scale Comparative Protein Structure Modeling
Select templates using permissive E-value
cutoff
Select templates using permissive E-value
cutoff
1
Expand match to cover complete
domains
Expand match to cover complete
domains
1
Build model for target segment by satisfaction of spatial
restraints
Build model for target segment by satisfaction of spatial
restraints
Evaluate modelEvaluate model
Align matched parts of sequence and structure
Align matched parts of sequence and structure
MO
DE
LL
ER
R. Sánchez & A. Šali, Proc. Natl. Acad. Sci. USA 95, 13597, 1998.N. Eswar, M. Marti-Renom, M.S. Madhusudhan, B. John, A. Fiser, R. Sánchez, F. Melo, N. Mirkovic, A. Šali.
Fo
r ea
ch t
arg
et s
equ
ence
Fo
r ea
ch t
emp
late
str
uct
ure
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ENDEND
http://salilab.org/modbasePieper et al., Nucl. Acids Res. 2002.
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Comparative modeling of the TrEMBL database
Unique sequences processed: 733,239
Sequences with fold assignments or models: 415,937 (57%)
4/03/02 ~4 weeks on 500 Pentium III CPUs
70% of models based on <30% sequence identity to template.
On average, only a domain per protein is modeled(an “average” protein has 2.5 domains of 175 aa).
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Model AccuracyMarti-Renom et al. Annu.Rev.Biophys.Biomol.Struct. 29, 291-325, 2000.