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282 J.D. Watson and J.M. Thorntonin Pfam (PF01979) which contains a number of deaminases and is part of a wideramidohydrolase superfamily clan. As an unknown function protein it was selectedfor analysis using ProFunc and the results indicated a probable match to one of the189 known enzyme active site templates used by the server.The enzyme match (with an e-value of 2.45 × 10 −4 ) is to the active site templatefor adenosine deaminase (EC 3.5.4.4) derived from PDB entry 1a4l, which is involvedin purine metabolism. The overall sequence identity between Tm0936 and this structure,based on a pairwise FASTA alignment, is only 24%, yet the structural similarity(calculated by ProFunc as the number of residue-pairs in the structural alignment thatlie in one or more fittable segments, as a percentage of the number of residues equivalencedby the alignment) is 95% indicating a high level of structural similarity. Withina 10 Å sphere of the template match the local sequence identity is 27.7% which indicatesthere is a higher level of similarity around the active site than throughout theentire protein. In addition to this strong match there are a number of reverse templatematches to other deaminases and amidohydrolases.The authors of the structure of Tm0936 had published a predicted function for thisprotein as an adenine deaminase (Hermann et al. 2007). The approach they usedinvolved structure-based targeted docking using metabolic intermediates which are ina high energy state, the principle being that docking initial substrates or products toenzymes may not be as effective as docking the intermediates that are stabilised by theenzyme. The resultant hit list of putative ligands was dominated by adenine analogues,appearing well-positioned to undergo C6-deamination. Four were tested as substrates,with three showing substantial catalytic rate constants. The structure of the complexbetween Tm0936 and the product (S-inosylhomocysteine) resulting from the deaminationof S-adenosylhomocysteine was determined. The enzyme template match showeda very close overlap between this bound ligand and the DCF ligand (deoxycoformycin,an inosine analogue) bound in the template structure of 1a4l (Fig. 11.1).Fold analysis using MSDfold picks up various amidohydrolases and guanine/cytosine deaminases. The reason that MSDfold did not identify the adenosinedeaminase structure as the best hit is that the Tm0936 structure has some additionalembellishments outside the core match. This resulted in the structural similarityfalling below the default cutoff of 70% of secondary structure elements required fora match (Fig. 11.2). This highlights the power of local comparisons and is an illustrativecase where function can be accurately identified by strong enzyme templatematches that could not have been identified by sequence methods alone.Another interesting case comes from the MCSG with the recent publication of thestructures of the open (R) and closed (T) states of prephenate dehydratase (PDT) (Tanet al. 2008), which have implications for our understanding of its allosteric regulationby L-phenylalanine and other amino acids. This enzyme (EC 4.2.1.51) converts prephenateto phenylpyruvate in l-phenylalanine biosynthesis. Its key role in the biosynthesisof l-Phe in organisms that utilize the shikimate pathway makes it an essentialenzyme in microorganisms. The fact that this enzyme is not found in humans meansit could serve as a possible drug target against microbial pathogens.The structures deposited in the PDB (2qmw and 2qmx) come from two differentorganisms and represent the first crystal structures of PDT in relaxed (R)
11 Function Predictions of Structural Genomics Results 283Fig. 11.1 Enzyme active site template match illustrating the overlap between the bound S-inosylhomocysteine(SIB) ligand in Tm0936 (orange sticks; PDB entry 2plm) and the deoxycoformycin(DCF) ligand, an inosine analogue, bound to a template structure derived from an adenosinedeaminase (purple sticks; PDB entry 1a41). The bound zinc atoms in both structures are displayedas overlapping spheres, the colouring following ligands bound to their respective proteins. Residuesfrom Tm0936 and adenosine deaminase are coloured blue and red, respectivelyFig. 11.2 Stereo view of the MSDfold superposition of the query structure (Tm0936, PDB entry2plm – coloured blue) with the structure used to generate the enzyme active site template (PDBentry 1a4l – coloured red). The additional secondary structure elements in the query protein canclearly be seen to the left of the image
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Daniel John RigdenEditorFrom Protei
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ContentsSection I Generating and In
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Contentsxi4.2.1 Alpha-Helical Bundl
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Contentsxiii7.4.2 Predicting Bindin
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Contentsxv12.3 Accuracy and Added V
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4 J. Lee et al.about 5.3 million pr
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6 J. Lee et al.Table 1.1 A list of
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8 J. Lee et al.2000; Sorin and Pand
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10 J. Lee et al.Although most knowl
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12 J. Lee et al.Fig. 1.3 Two exampl
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14 J. Lee et al.rugged containing m
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16 J. Lee et al.1.3.4 Mathematical
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18 J. Lee et al.potentials, each re
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20 J. Lee et al.viewpoint of struct
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22 J. Lee et al.Hsieh MJ, Luo R (20
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24 J. Lee et al.Sippl MJ (1990) Cal
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Chapter 2Fold RecognitionLawrence A
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2 Fold Recognition 29It has long be
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2 Fold Recognition 31Fig. 2.2 Graph
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2 Fold Recognition 33distribute the
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2 Fold Recognition 35Table 2.1 (a)
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2 Fold Recognition 37dependent on t
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2 Fold Recognition 39based on the r
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2 Fold Recognition 41The idea of co
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2 Fold Recognition 43query sequence
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2 Fold Recognition 452.3.4 Consensu
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2 Fold Recognition 472.4 Alignment
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2 Fold Recognition 49statistical me
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2 Fold Recognition 51methods (e.g.
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2 Fold Recognition 53Berman HM, Wes
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2 Fold Recognition 55Tress ML, Jone
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58 A. Fiserwith more than 50% seque
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60 A. FiserIn contrast to ab initio
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62 A. FiserTable 3.1 (continued)SWI
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64 A. Fiserbetween fold recognition
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66 A. FiserFig. 3.1 Comparing accur
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68 A. Fiserinto conserved core regi
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70 A. Fiseralignments are built and
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72 A. Fiserfold, such as the hyperv
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74 A. Fiserfunctions delivers impro
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76 A. Fiserfrom efforts of genome s
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78 A. FiserA rigorous statistical e
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80 A. Fiser(Clore et al. 1993). Cha
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82 A. FiserImproved and new methods
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84 A. FiserClaessens M, Van Cutsem
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86 A. FiserHavel TF, Snow ME (1991)
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88 A. FiserPetrey D, Xiang Z, Tang
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90 A. Fiservan Vlijmen HW, Karplus
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92 T. Nugent and D.T. Jones4.2 Stru
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94 T. Nugent and D.T. JonesFig. 4.2
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96 T. Nugent and D.T. JonesTable 4.
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98 T. Nugent and D.T. Jones2000), d
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100 T. Nugent and D.T. JonesTable 4
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102 T. Nugent and D.T. JonesFig. 4.
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104 T. Nugent and D.T. JonesFig. 4.
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106 T. Nugent and D.T. Jonessubdivi
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108 T. Nugent and D.T. Jonescomplex
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110 T. Nugent and D.T. JonesMartell
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Chapter 5Bioinformatics Approaches
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5 Structure and Function of Intrins
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Chapter 6Function Diversity Within
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6 Function Diversity Within Folds a
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Chapter 7Predicting Protein Functio
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7 Predicting Protein Function from
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Table 7.1 Online resources and tool
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Chapter 83D MotifsElaine C. Meng, B
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8 3D Motifs 189clustering similar s
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8 3D Motifs 191To improve the signa
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8 3D Motifs 193structures together.
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8 3D Motifs 195Table 8.1 (continued
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8 3D Motifs 1978.3.1 User-Defined M
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8 3D Motifs 199Fig. 8.3 The FFF mot
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8 3D Motifs 2018.3.2 Motif Discover
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8 3D Motifs 203In addition to SITE
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8 3D Motifs 205folds; they shared a
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8 3D Motifs 207from a training set
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8 3D Motifs 209Table 8.3 Web server
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8 3D Motifs 211its greater overall
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8 3D Motifs 213Ideally, a 3D motif
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8 3D Motifs 215Ivanisenko VA, Pintu
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Chapter 9Protein Dynamics: From Str
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9 Protein Dynamics: From Structure
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Page 258 and 259: 252 R.A. LaskowskiConsequently, man
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Page 268 and 269: 262 R.A. Laskowskiaccessibility and
Page 270 and 271: 264 R.A. LaskowskiFig. 10.6 A ligan
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Page 276 and 277: 270 R.A. LaskowskiReferencesAltschu
Page 278 and 279: 272 R.A. LaskowskiXenarios I, Salwi
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Page 298 and 299: Chapter 12Prediction of Protein Fun
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Page 324 and 325: 320 IndexConsensus templates, 205Co
Page 326 and 327: 322 IndexLigand-binding templates,
Page 328: 324 IndexStructure-function linkage
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