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Spencer Bliven 
September 30, 2014 
jLBR Seminar
1 
From Google Earth. Data SIO, NOAA, U.S. Navy, NGA, 
GEBCO, Image Landsat, Image IBCAO
d2hmva1 
2 
PDP:PDP:d2r4qa1 
PDP:3A1DAa 
d1djla_ 
PDP:2VOYIa 
d1shux_ 
d1d4oa_ 
! What’s the nature of protein fold space?...
Hemoglobin 
[PDB:4HHB] 
C2 
Rhinovirus 2 
[3DPR] 
Icosahedral 
GTP 
Cyclohydrolase I 
[1A8R] 
D5 
AmtB Ammonia 
Channel 
[...
Ferredoxin-like 
[SCOP:d2j5aa1] 
C2 
Beta-Propeller 
[SCOP:d1u6dx_] 
C6 
Beta-trefoil 
[3JUT] 
C3 
TIM barrel 
[1TIM] 
C8 ...
! Function 
! Allosteric regulation/cooperativity 
! Bind ligands symmetrically (e.g. 
metals, palindromic DNA, 
channels)...
! Function 
! Allosteric regulation/cooperativity 
! Bind ligands symmetrically (e.g. 
metals, palindromic DNA, 
channels)...
! Evolution 
! Identify duplications & fusions 
! Many examples of homologous quaternary symmetric/ 
internally symmetric ...
E. Coli DNA polymerase III beta 
subunit 
! 2 chains (C2 crystal axis) 
Human proliferating cell nuclear 
antigen 
! 3 cha...
E. Coli DNA polymerase III beta 
subunit 
! 2 chains 
! 6 domains (pseudo C6) 
Human proliferating cell nuclear 
antigen 
...
! 2-3 chains 
! 6 domains 
! 12 structural repeats (pseudo D6) 
Ancient 12-mer? 
Ancient 6-mer 
Eukaryotic/Archaeal/ Bacte...
Glyoxalase I from 
Clostridium 
acetobutylicum [3HDP] 
(Nickel; Dimer) 
Glyoxalase I from E. 
coli [1F9Z] 
(Nickel; Dimer)...
12 
Glyoxalase I from 
Clostridium 
acetobutylicum [3HDP] 
(Nickel; Dimer) 
Glyoxalase I from E. 
coli [1F9Z] 
(Nickel; Di...
! Extends Combinatorial 
Extension (CE) algorithm for 
structural alignment 
! Web server: source.rcsb.org/ 
jfatcatserver...
14 
PDB:1MER Chain A
! 1007 structures from 
SCOP superfamilies 
! Manually curated 
! Excludes small proteins 
(<4 SSEs) 
! 24% of superfamili...
! AUC = .95 
! 86% True Positive 
Rate 
! 3.3% False 
Positive Rate 
SymD: 
Kim, C., Basner, J., & Lee, B. (2010). BMC 
Bi...
! All domains from SCOPe 2.03 
! Interactive results: 
source.rcsb.org/jfatcatserver/scopResults.jsp 
! Underestimate base...
Periplasmic-binding protein 
Nucleotide-binding domain 
18 
BtuF 
BtuC 
BtuD 
Transmembrane domain 
Vitamin B12 transporte...
19 
BtuF 
BtuC 
BtuD 
Vitamin B12 transporter BtuCD–F from E. coli [4FI3]
20 
BtuF [1N4A] 
BtuF 
BtuC 
BtuD 
Vitamin B12 transporter BtuCD–F from E. coli [4FI3]
! PTS sorbitol transporter subunit IIA 
! Novel fold 
! Solved by the Protein Structure Initiative 
! Structural alignment...
22 
! Systematically compare 
symmetry units across 
the PDB 
! CE-Symm 
improvements 
! Improve order detection 
(C8, not...
! Paul Scherrer Institute 
! Guido Capitani 
! Kumaran Baskaran 
! Jose Duarte 
! Joseph Somody 
! LBR members 
! UC San D...
! Racemases and epimerases are enriched 
25
4 
3 
2 
1 
0 
0.00 0.25 0.50 0.75 
TM−Score 
Density 
Asymmetric 
Symmetric 
26
120° 120° 
Fibroblast Growth 
Factor [3JUT] 
Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P...
120° 120° 
Fibroblast Growth 
Factor [3JUT] 
Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P...
This work is licensed under a 
Creative Commons Attribution-ShareAlike 3.0 Unported License. 
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CE-Symm jLBR talk

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Slides from my talk describing CE-Symm and my research on internal symmetry. It was given for jLBR, the weekly seminar series for our department at PSI.

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CE-Symm jLBR talk

  1. 1. Spencer Bliven September 30, 2014 jLBR Seminar
  2. 2. 1 From Google Earth. Data SIO, NOAA, U.S. Navy, NGA, GEBCO, Image Landsat, Image IBCAO
  3. 3. d2hmva1 2 PDP:PDP:d2r4qa1 PDP:3A1DAa d1djla_ PDP:2VOYIa d1shux_ d1d4oa_ ! What’s the nature of protein fold space? ! How do new folds evolve? d1nrjb_ ! How do gene rearrangements relate to protein structure? ! What can internal symmetry tell us about protein function and evolution? ! What algorithms are best for detecting remote homology? PDP:2IYEAa PDP:3QJGAa PDP:2FN9Aa d1wa5a_ PDP:3QELBa PDP:3RBZAb d1id1a_ PDP:2WI8Aa PDP:3IPCAa d1ls1a2 SCOP:d1su3a2 d1pt2a_ d1c5ka1 d1k3ia3 d1h9ya2
  4. 4. Hemoglobin [PDB:4HHB] C2 Rhinovirus 2 [3DPR] Icosahedral GTP Cyclohydrolase I [1A8R] D5 AmtB Ammonia Channel [1U7G] C3 3
  5. 5. Ferredoxin-like [SCOP:d2j5aa1] C2 Beta-Propeller [SCOP:d1u6dx_] C6 Beta-trefoil [3JUT] C3 TIM barrel [1TIM] C8 Key: Crystallographic/NCS axis Pseudosymmetry axis 4
  6. 6. ! Function ! Allosteric regulation/cooperativity ! Bind ligands symmetrically (e.g. metals, palindromic DNA, channels) Monod, J., Wyman, J., & Changeux, J.-P. (1965). J Mol Biol, 12, 88–118. Hemoglobin [4HHB] TATA Binding Protein 5 [1TGH]
  7. 7. ! Function ! Allosteric regulation/cooperativity ! Bind ligands symmetrically (e.g. metals, palindromic DNA, channels) ! Folding ! Prevent infinite assembly ! Subunits fold quasi-independently TATA Binding Protein [1TGH] Monod, J., Wyman, J., & Changeux, J.-P. (1965). J Mol Biol, 12, 88–118. Wolynes, P. G. (1996). PNAS, 93(25), 14249–14255. 6 Hemoglobin [4HHB]
  8. 8. ! Evolution ! Identify duplications & fusions ! Many examples of homologous quaternary symmetric/ internally symmetric proteins ! Tradeoff between monomer & oligomer Lee and Blaber. PNAS (2011) vol. 108 (1) pp. 126-30 7 3OL0 3O49
  9. 9. E. Coli DNA polymerase III beta subunit ! 2 chains (C2 crystal axis) Human proliferating cell nuclear antigen ! 3 chains (C3 crystal axis) 1MMI 1VYM 8
  10. 10. E. Coli DNA polymerase III beta subunit ! 2 chains ! 6 domains (pseudo C6) Human proliferating cell nuclear antigen ! 3 chains ! 6 domains (pseudo C6) 1MMI 1VYM 9
  11. 11. ! 2-3 chains ! 6 domains ! 12 structural repeats (pseudo D6) Ancient 12-mer? Ancient 6-mer Eukaryotic/Archaeal/ Bacterial Dimer Viral Trimer Kelman, Z., & O'Donnell, M. (1995). Nucleic Acids Research, 23(18), 3613–3620. Neuwald, A. F., & Poleksic, A. (2000). Nucleic Acids Research, 28(18), 3570–3580. 10
  12. 12. Glyoxalase I from Clostridium acetobutylicum [3HDP] (Nickel; Dimer) Glyoxalase I from E. coli [1F9Z] (Nickel; Dimer) 1,2-dihydroxy-naphthalene dioxygenase from Pseudomonas sp. strain C18 [2EHZ] (Iron; Octamer) 11
  13. 13. 12 Glyoxalase I from Clostridium acetobutylicum [3HDP] (Nickel; Dimer) Glyoxalase I from E. coli [1F9Z] (Nickel; Dimer) 1,2-dihydroxy-naphthalene dioxygenase from Pseudomonas sp. strain C18 [2EHZ] (Iron; Octamer)
  14. 14. ! Extends Combinatorial Extension (CE) algorithm for structural alignment ! Web server: source.rcsb.org/ jfatcatserver/symmetry.jsp ! Download & Source code: github.com/rcsb/symmetry (LGPL) ! Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P., Bourne, P. E., & Prlić, A. (2014). Systematic Detection of Internal Symmetry in Proteins Using CE-Symm. Journal of Molecular Biology, 426(11), 2255–2268. 13
  15. 15. 14 PDB:1MER Chain A
  16. 16. ! 1007 structures from SCOP superfamilies ! Manually curated ! Excludes small proteins (<4 SSEs) ! 24% of superfamilies have internal symmetry or large structural repeats Order Superfamilies % Asymmetric 766 76.10% Rotational 2 166 16.5% 3 10 1.0% 4 2 0.2% 5 3 0.3% 6 9 0.9% 7 9 0.9% 8 21 2.1% Dihedral 2 2 0.2% 4 1 0.1% Helical 2 9 0.9% 3 2 0.2% Non-integral 2 0.2% Superhelical 2 0.2% Translational 3 0.3% 15
  17. 17. ! AUC = .95 ! 86% True Positive Rate ! 3.3% False Positive Rate SymD: Kim, C., Basner, J., & Lee, B. (2010). BMC Bioinformatics, 11, 303. 16
  18. 18. ! All domains from SCOPe 2.03 ! Interactive results: source.rcsb.org/jfatcatserver/scopResults.jsp ! Underestimate based on conservative thresholds SCOP Class Superfamilies % Symmetric α 507 18.5% β 354 24.6% α/β 244 16.8% α+β 551 14.3% Membrane 109 23.8% Overall 1831 18.0% 17
  19. 19. Periplasmic-binding protein Nucleotide-binding domain 18 BtuF BtuC BtuD Transmembrane domain Vitamin B12 transporter BtuCD–F from E. coli [4FI3]
  20. 20. 19 BtuF BtuC BtuD Vitamin B12 transporter BtuCD–F from E. coli [4FI3]
  21. 21. 20 BtuF [1N4A] BtuF BtuC BtuD Vitamin B12 transporter BtuCD–F from E. coli [4FI3]
  22. 22. ! PTS sorbitol transporter subunit IIA ! Novel fold ! Solved by the Protein Structure Initiative ! Structural alignment reveals a conserved sequence motif between halves 2F9H 21
  23. 23. 22 ! Systematically compare symmetry units across the PDB ! CE-Symm improvements ! Improve order detection (C8, not C4 or C2) ! Visualization & usability ! Find mixed quaternary & internal symmetry
  24. 24. ! Paul Scherrer Institute ! Guido Capitani ! Kumaran Baskaran ! Jose Duarte ! Joseph Somody ! LBR members ! UC San Diego/RCSB ! Douglas Myers-Turnbull ! Andreas Prlić ! Peter Rose ! Zaid Aziz ! RCSB & Bourne Lab members ! NIH ! Philip Bourne ! Philippe Youkharibache ! David Landsman Resources: ! source.rcsb.org/jfatcatserver/ symmetry.jsp ! github.com/rcsb/symmetry ! www.slideshare.net/sbliven Funding: NSF, NIH, DOE, Open Science Grid 23
  25. 25. ! Racemases and epimerases are enriched 25
  26. 26. 4 3 2 1 0 0.00 0.25 0.50 0.75 TM−Score Density Asymmetric Symmetric 26
  27. 27. 120° 120° Fibroblast Growth Factor [3JUT] Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P., Bourne, P. E., & Prlić, A. (2014). Journal of Molecular Biology, 426(11), 2255–2268. 27
  28. 28. 120° 120° Fibroblast Growth Factor [3JUT] Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P., Bourne, P. E., & Prlić, A. (2014). Journal of Molecular Biology, 426(11), 2255–2268. 28
  29. 29. This work is licensed under a Creative Commons Attribution-ShareAlike 3.0 Unported License. 29

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