User:James D Watson/Structural Templates: Difference between revisions

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The example structure shown to <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_highlight/1'>illustrate the motif</scene> is that of Zif268 protein-DNA complex from Mus musculus (PDB entry 1AAY). In this example (a C2H2 class zinc finger) the conserved <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_cysteine/1'>cysteine</scene> and <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_histidine/1'>histidine</scene> residues form ligands to a <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_zn/1'>zinc ion</scene> whose coordination is essential to stabilise the tertiary fold of the protein. The fold is important because it helps orientate the <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_recognition/1'>recogniton helices</scene> to bind to the <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_major_groove/1'>major groove of the DNA</scene>.

The example structure shown to <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_highlight/1'>illustrate the motif</scene> is that of Zif268 protein-DNA complex from Mus musculus (PDB entry 1AAY). In this example (a C2H2 class zinc finger) the conserved <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_cysteine/1'>cysteine</scene> and <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_histidine/2'>histidine</scene> residues form ligands to a <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_zn/1'>zinc ion</scene> whose coordination is essential to stabilise the tertiary fold of the protein. The fold is important because it helps orientate the <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_recognition/1'>recogniton helices</scene> to bind to the <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_major_groove/1'>major groove of the DNA</scene>.

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==Nests==

Smaller than loops and turns are some recently discovered motifs known as "nests". These are mainchain conformations where 3 successive amide groups form a positively charged concavity capable of binding one or more negatively charged atoms (Figure 1). They are characterised by alternating enantiomeric mainchain dihedral angles from the alpha and gamma regions of the Ramachandran plot, and can be of RL (right handed - left handed) or LR type. They are most commonly found as part of previously described hydrogen bonded structural motifs but are also found at functional sites.<br>

<br>

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In compound nests the result is a long chain with all the overlapping nests facing a similar direction. This basically forms a much wider nest that is capable of binding a larger anionic group of atoms such as the phosphate ion, and are usually functionally important motifs. Tandem nests are not as common and, due to the greater change in the direction that adjacent nests face, only seem to perform functional roles when found in conjunction with one or more compound nests.

One of the most well known functional compound nests is found in the phosphate-binding loop of Ras protein (PDB entry 5p21). The P-loop is a well described ATP- or GTP-binding loop present in a large superfamily of important proteins which includes G-proteins and kinases. The main feature of the P-loop is a long compound LRLR nest that forms a binding site for the β-phosphate of ATP or GTP. However, this is an example of a motif where the ligand also binds to the free main chain NH groups at the N-terminus of an alpha helix. On closer inspection it becomes evident that this interaction is in addition to the compound nest and does not interfere with it. Therefore the P-loop is actually more accurately described as a compound LRLR nest and an adjacent helical N-terminus that collectively bind to the α- and β-phosphates of the GDP substrate. The P-loop, which is retained throughout the superfamily, has a highly conserved GxxxxGKS/T consensus sequence (where the xxGK section forms the LRLR compound nest).

One of the most well known functional compound nests is found in the phosphate-binding loop of Ras protein (PDB entry 5p21). The <scene name='User:James_D_Watson/Structural_Templates/Secondary_structure_ploop/1'>P-loop</scene> is a well described ATP- or GTP-binding loop present in a large superfamily of important proteins which includes G-proteins and kinases. The main feature of the P-loop is a long compound LRLR nest that <scene name='User:James_D_Watson/Structural_Templates/Secondary_structure_ploop_nest/1'>forms a binding site for the β-phosphate of ATP or GTP</scene>. However, this is an example of a motif where the ligand also binds to the free main chain NH groups at the N-terminus of an alpha helix. On closer inspection it becomes evident that this interaction is in addition to the compound nest and does not interfere with it. Therefore the P-loop is actually more accurately described as a compound LRLR nest and an adjacent helical N-terminus that collectively bind to the α- and β-phosphates of the GDP substrate. The P-loop, which is retained throughout the superfamily, has a highly conserved GxxxxGKS/T consensus sequence (where the xxGK section forms the LRLR compound nest).

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Moving away from secondary structure elements, loop and nests, another type of structural motif is that of enzyme active sites. These structural motifs are usually more difficult to detect as they can be discontinuous, often involving elements widely spaced along the sequence. One such example is that of the "catalytic triad" of the serine proteases.

Serine proteases are found in a number of organisms but common to their function is the hydrolysis of peptide bonds. These enzymes catalyse the reaction using a highly reactive serine residue to attack the carbonyl group of the backbone to be hydrolysed. The chemistry of this reaction and the regeneration of the active site, requires the presence of the Ser-His-Asp catalytic triad. In chymotrypsin these residues are (Ser-195, His-57 and Asp-102) whereas in the bacterial subtilisin the site is formed by (Ser-221, His-64 and Asp-32). These two proteins are evolutionary unrelated and this is the classic example of convergent evolution to solve the problem of peptide bond hydrolysis.

Serine proteases are found in a number of organisms but common to their function is the hydrolysis of peptide bonds. These enzymes catalyse the reaction using a highly reactive serine residue to attack the carbonyl group of the backbone to be hydrolysed. The chemistry of this reaction and the regeneration of the active site, requires the presence of the Ser-His-Asp catalytic triad. In chymotrypsin (PDB entry [[1ab9]]) these residues are (Ser-195, His-57 and Asp-102) whereas in the bacterial subtilisin (PDB entry [[1st2]]) the site is formed by (Ser-221, His-64 and Asp-32). These two proteins are evolutionary unrelated and this is the classic example of convergent evolution to solve the problem of peptide bond hydrolysis.

The detection of these types of motif is almost impossible by looking at the amino acid sequence: there is no evolutionary relationship to detect, the residues are ordered differently in the sequence, and the spacing between the residues also varies. These motifs can be detected relativeley easily using structural comparison, particularly ~~the~~ template-based motif detection algorithms ~~(some of which are listed in table 2 below)~~. The subtilisin and chymotrypsin ~~catalytic triads~~ are shown ~~superposed here~~ - note that the global folds of these two proteins are very different so the site could not have been detected using such methods.

The detection of these types of motif is almost impossible by looking at the amino acid sequence: there is no evolutionary relationship to detect, the residues are ordered differently in the sequence, and the spacing between the residues also varies. These motifs can be detected relativeley easily using structural comparison, particularly template-based motif detection algorithms. The subtilisin and chymotrypsin structures are shown side by side - note that the global folds of these two proteins are very different so the site could not have been detected using such methods. Click to see the catalytic triad in <scene name='User:James_D_Watson/Structural_Templates/Subtilisin_startpoint_catalyti/1' target='subtilisin'>subtilisin</scene> and <scene name='User:James_D_Watson/Structural_Templates/Chymotrypsin_start_triad/1' target='chymotrypsin'>chymotrypsin</scene> respectively.

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-The example structure shown to <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_highlight/1'>illustrate the motif</scene> is that of Zif268 protein-DNA complex from Mus musculus (PDB entry 1AAY). In this example (a C2H2 class zinc finger) the conserved <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_cysteine/1'>cysteine</scene> and <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_histidine/1'>histidine</scene> residues form ligands to a <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_zn/1'>zinc ion</scene> whose coordination is essential to stabilise the tertiary fold of the protein. The fold is important because it helps orientate the <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_recognition/1'>recogniton helices</scene> to bind to the <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_major_groove/1'>major groove of the DNA</scene>.
+The example structure shown to <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_highlight/1'>illustrate the motif</scene> is that of Zif268 protein-DNA complex from Mus musculus (PDB entry 1AAY). In this example (a C2H2 class zinc finger) the conserved <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_cysteine/1'>cysteine</scene> and <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_histidine/2'>histidine</scene> residues form ligands to a <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_zn/1'>zinc ion</scene> whose coordination is essential to stabilise the tertiary fold of the protein. The fold is important because it helps orientate the <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_recognition/1'>recogniton helices</scene> to bind to the <scene name='User:James_D_Watson/Structural_Templates/Zinc_finger_major_groove/1'>major groove of the DNA</scene>.
 {{Clear}}
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 ==Nests==
 Smaller than loops and turns are some recently discovered motifs known as "nests". These are mainchain conformations where 3 successive amide groups form a positively charged concavity capable of binding one or more negatively charged atoms (Figure 1). They are characterised by alternating enantiomeric mainchain dihedral angles from the alpha and gamma regions of the Ramachandran plot, and can be of RL (right handed - left handed) or LR type. They are most commonly found as part of previously described hydrogen bonded structural motifs but are also found at functional sites.<br>
 <br>
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 In compound nests the result is a long chain with all the overlapping nests facing a similar direction.  This basically forms a much wider nest that is capable of binding a larger anionic group of atoms such as the phosphate ion, and are usually functionally important motifs. Tandem nests are not as common and, due to the greater change in the direction that adjacent nests face, only seem to perform functional roles when found in conjunction with one or more compound nests.
-One of the most well known functional compound nests is found in the phosphate-binding loop of Ras protein (PDB entry 5p21). The P-loop is a well described ATP- or GTP-binding loop present in a large superfamily of important proteins which includes G-proteins and kinases. The main feature of the P-loop is a long compound LRLR nest that forms a binding site for the β-phosphate of ATP or GTP. However, this is an example of a motif where the ligand also binds to the free main chain NH groups at the N-terminus of an alpha helix. On closer inspection it becomes evident that this interaction is in addition to the compound nest and does not interfere with it. Therefore the P-loop is actually more accurately described as a compound LRLR nest and an adjacent helical N-terminus that collectively bind to the α- and β-phosphates of the GDP substrate. The P-loop, which is retained throughout the superfamily, has a highly conserved GxxxxGKS/T consensus sequence (where the xxGK section forms the LRLR compound nest).
+<applet load='1lmb' size='300' frame='true' align='left' caption='Nest in PDB entry 5p21' scene='User:James_D_Watson/Structural_Templates/Secondary_structure_start/4'/>
+One of the most well known functional compound nests is found in the phosphate-binding loop of Ras protein (PDB entry 5p21). The <scene name='User:James_D_Watson/Structural_Templates/Secondary_structure_ploop/1'>P-loop</scene> is a well described ATP- or GTP-binding loop present in a large superfamily of important proteins which includes G-proteins and kinases. The main feature of the P-loop is a long compound LRLR nest that <scene name='User:James_D_Watson/Structural_Templates/Secondary_structure_ploop_nest/1'>forms a binding site for the β-phosphate of ATP or GTP</scene>. However, this is an example of a motif where the ligand also binds to the free main chain NH groups at the N-terminus of an alpha helix. On closer inspection it becomes evident that this interaction is in addition to the compound nest and does not interfere with it. Therefore the P-loop is actually more accurately described as a compound LRLR nest and an adjacent helical N-terminus that collectively bind to the α- and β-phosphates of the GDP substrate. The P-loop, which is retained throughout the superfamily, has a highly conserved GxxxxGKS/T consensus sequence (where the xxGK section forms the LRLR compound nest).
 {{Clear}}
@@ Line 106: / Line 107: @@
 Moving away from secondary structure elements, loop and nests, another type of structural motif is that of enzyme active sites. These structural motifs are usually more difficult to detect as they can be discontinuous, often involving elements widely spaced along the sequence. One such example is that of the "catalytic triad" of the serine proteases.
-Serine proteases are found in a number of organisms but common to their function is the hydrolysis of peptide bonds. These enzymes catalyse the reaction using a highly reactive serine residue to attack the carbonyl group of the backbone to be hydrolysed. The chemistry of this reaction and the regeneration of the active site, requires the presence of the Ser-His-Asp catalytic triad. In chymotrypsin these residues are (Ser-195, His-57 and Asp-102) whereas in the bacterial subtilisin the site is formed by (Ser-221, His-64 and Asp-32). These two proteins are evolutionary unrelated and this is the classic example of convergent evolution to solve the problem of peptide bond hydrolysis.
+Serine proteases are found in a number of organisms but common to their function is the hydrolysis of peptide bonds. These enzymes catalyse the reaction using a highly reactive serine residue to attack the carbonyl group of the backbone to be hydrolysed. The chemistry of this reaction and the regeneration of the active site, requires the presence of the Ser-His-Asp catalytic triad. In chymotrypsin (PDB entry [[1ab9]]) these residues are (Ser-195, His-57 and Asp-102) whereas in the bacterial subtilisin (PDB entry [[1st2]]) the site is formed by (Ser-221, His-64 and Asp-32). These two proteins are evolutionary unrelated and this is the classic example of convergent evolution to solve the problem of peptide bond hydrolysis.
-The detection of these types of motif is almost impossible by looking at the amino acid sequence: there is no evolutionary relationship to detect, the residues are ordered differently in the sequence, and the spacing between the residues also varies. These motifs can be detected relativeley easily using structural comparison, particularly the template-based motif detection algorithms (some of which are listed in table 2 below). The subtilisin and chymotrypsin catalytic triads are shown superposed here - note that the global folds of these two proteins are very different so the site could not have been detected using such methods.
+The detection of these types of motif is almost impossible by looking at the amino acid sequence: there is no evolutionary relationship to detect, the residues are ordered differently in the sequence, and the spacing between the residues also varies. These motifs can be detected relativeley easily using structural comparison, particularly template-based motif detection algorithms. The subtilisin and chymotrypsin structures are shown side by side - note that the global folds of these two proteins are very different so the site could not have been detected using such methods. Click to see the catalytic triad in <scene name='User:James_D_Watson/Structural_Templates/Subtilisin_startpoint_catalyti/1' target='subtilisin'>subtilisin</scene> and <scene name='User:James_D_Watson/Structural_Templates/Chymotrypsin_start_triad/1' target='chymotrypsin'>chymotrypsin</scene> respectively.
+<applet load='1st2' size='300' frame='true' align='left' caption='Subtilisin 1st2' scene='User:James_D_Watson/Structural_Templates/Subtilisin_startpoint/1' name='subtilisin' />
+<applet load='1st2' size='300' frame='true' align='right' caption='Chymotrypsin 1ab9' scene='User:James_D_Watson/Structural_Templates/Chymotrypsin_start/1' name='chymotrypsin' />