Sandbox Reserved 932: Difference between revisions

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B. Dendrophila monomeric toxin (Denmotoxin) is the primary protein of snake venom used by Boiga dendrophila. This colubrid snake lives in Southest Asian lowland rainforest and mangrove swamps using birds as its primary prey.

B. Dendrophila monomeric toxin (Denmotoxin) is the primary protein of snake venom used by ''Boiga dendrophila'' (fig. 1). This colubrid snake lives in Southest Asian lowland rainforest and mangrove swamps using birds as its primary prey.

One of the most well characterized snake venom protein families is the Three-finger-toxins (3FTX). These proteins consist of three β-stranded finger-like polypeptide loops stabilized by four disulphide bridges on the surface of a globular core. In non-convential 3TFXs a fifth disulphide bridge can be present as is the case in Denmotoxin. The crystal structure of denmotoxin was solved to 1.9Å by molecular replacement method.

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caption='Structure of denmotoxin (PDB entry [[2H5F]])' scene='57/579702/Main_view/2'>

[[Image:Mangrove snake.jpg‎|300px|right|thumb| Mangrove catsnake]]

[[Image:Mangrove snake.jpg‎|300px|right|thumb|Figure 1. Mangrove catsnake]]

[[Image:Kolme_sormea_figure_text.png‎|300px|right|thumb| Three fingers formed by three peptide loops (F1, F2 & F3) [PDB=2H5F]]]

[[Image:Kolme_sormea_figure_text.png‎|300px|right|thumb| Figure 2. Three fingers formed by three peptide loops (F1, F2 & F3) [PDB=2H5F]]]

Denmotoxin is a snake venom protein produced by ''Boiga dendrophila'' ([http://en.wikipedia.org/wiki/Boiga_dendrophila mangrove catsnake]) which belongs to a family of well studied three-fingered neurotoxins.

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Denmotoxin is a monomeric protein comprising of 77 amino acid residues. Denmotoxin consists of <scene name='57/579702/Three_fingers/1'>three polypeptide loops</scene> protruding from the <scene name='57/579702/3ftx_beta_strands/2'>globular core</scene>; this structure is typical for 3FTXs. The globular core consists of a triple stranded anti-parallel β-sheet ; two of the β-strands in this structure connect to the second loop (central loop) and one β-strand connects to the third loop. There are two highly <scene name='57/579702/Flexible_regions/2'>flexible regions</scene> on the protein: one at the tip of the central loop and one at the 3 first residues of the N-terminus; the expected active site of denmotoxin is at the tip of the central loop.

Denmotoxin is a monomeric protein comprising of 77 amino acid residues. Denmotoxin consists of <scene name='57/579702/Three_fingers/1'>three polypeptide loops</scene> (fig. 2) protruding from the <scene name='57/579702/3ftx_beta_strands/2'>globular core</scene>; this structure is typical for 3FTXs. The globular core consists of a triple stranded anti-parallel β-sheet ; two of the β-strands in this structure connect to the second loop (central loop) and one β-strand connects to the third loop. There are two highly <scene name='57/579702/Flexible_regions/2'>flexible regions</scene> on the protein: one at the tip of the central loop and one at the 3 first residues of the N-terminus; the expected active site of denmotoxin is at the tip of the central loop.

There are 10 structurally important cysteine-residues in denmotoxin which form five stabilizing <scene name='57/579702/Disulphides/3'>disulphide bonds</scene>. Four of these disulphide bonds, which are found in all 3FTXs are located at the central core and the fifth additional bond is found at the tip of the first loop. The cysteine residues of all 3FTXs are highly conserved, whereas the other residues within the sequence express high variability. Denmotoxin possesses most of the conserved residues invariant among 3FTXs which have been shown to be important for the proper folding of and structure of protein. The presence of these structurally important residues result in the characteristic three finger fold of the toxin (e.g. Gly52, Pro58).

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[[Image:Bungarotoxin interaction with nACHr figure text.png‎|300px|right|thumb| Suggested interaction of '''α-bungarotoxin''' in binding pocket of nAChR (simplified figure) [PDB=4HQP]]]

[[Image:Bungarotoxin interaction with nACHr figure text.png‎|300px|right|thumb| Figure 3. Suggested interaction of '''α-bungarotoxin''' in binding pocket of nAChR (simplified figure) [PDB=4HQP]]]

Most of the 3FTX family proteins possess a highly conserved arginine in the tip of their binding loop responsible for interaction with nAChRs. This interaction was determined by resolving a structure of α7 nAChR chimera in a complex with α-bungarotoxin (~~see~~ fig.). In denmotoxin, this loop contains several changes in its sequence; arginine has replaced by aspartic acid (ASP41) and two additional glutamates (GLU42 & GLU45) generate untypical <scene name='57/579702/Negative_charge/1'>negative charge</scene> into the loop.

Most of the 3FTX family proteins possess a highly conserved arginine in the tip of their binding loop responsible for interaction with nAChRs. This interaction was determined by resolving a structure of α7 nAChR chimera in a complex with α-bungarotoxin (fig. 3). In denmotoxin, this loop contains several changes in its sequence; arginine has replaced by aspartic acid (ASP41) and two additional glutamates (GLU42 & GLU45) generate untypical <scene name='57/579702/Negative_charge/1'>negative charge</scene> into the loop.

Biochemistry of denmotoxin is unique for its taxon specificity to bird nicotinic acetylcholine receptors (nAChR). Binding of denmotoxin to chick muscle AChR (α1βγδ) is a highly irreversible whereas interaction with identical subunit assembly in mouse AChR is reversible. The reversible binding allows the receptor to function properly, but in the case of irreversible binding nAChR is prevented of natural agonist activation. Previous studies <ref>Samson. A. O. & Levitt M., [http://pubs.acs.org/doi/abs/10.1021/bi702272j "Inhibition Mechanism of the Acetylcholine Receptor by α-Neurotoxins as Revealed by Normal-Mode Dynamics"], ''Biochemistry, 2008, 47 (13), pp 4065–4070'', March 8, 2008. Retrieved May 19, 2014.</ref> with 3FTXs have shown that the binding of toxin leads to “locking down” of the nACh receptor, preventing required conformational change for ion channel activation and induction of signal.

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@@ Line 4: / Line 4: @@
-B. Dendrophila monomeric toxin (Denmotoxin) is the primary protein of snake venom used by Boiga dendrophila. This colubrid snake lives in Southest Asian lowland rainforest and mangrove swamps using birds as its primary prey.
+B. Dendrophila monomeric toxin (Denmotoxin) is the primary protein of snake venom used by ''Boiga dendrophila'' (fig. 1). This colubrid snake lives in Southest Asian lowland rainforest and mangrove swamps using birds as its primary prey.
 One of the most well characterized snake venom protein families is the Three-finger-toxins (3FTX). These proteins consist of three β-stranded finger-like polypeptide loops stabilized by four disulphide bridges on the surface of a globular core. In non-convential 3TFXs a fifth disulphide bridge can be present as is the case in Denmotoxin. The crystal structure of denmotoxin was solved to 1.9Å by molecular replacement method.
@@ Line 13: / Line 13: @@
 caption='Structure of denmotoxin (PDB entry [[2H5F]])' scene='57/579702/Main_view/2'>
-[[Image:Mangrove snake.jpg‎|300px|right|thumb| Mangrove catsnake]]
+[[Image:Mangrove snake.jpg‎|300px|right|thumb|Figure 1. Mangrove catsnake]]
-[[Image:Kolme_sormea_figure_text.png‎|300px|right|thumb| Three fingers formed by three peptide loops (F1, F2 & F3) [PDB=2H5F]]]
+[[Image:Kolme_sormea_figure_text.png‎|300px|right|thumb| Figure 2. Three fingers formed by three peptide loops (F1, F2 & F3) [PDB=2H5F]]]
 Denmotoxin is a snake venom protein produced by ''Boiga dendrophila'' ([http://en.wikipedia.org/wiki/Boiga_dendrophila mangrove catsnake]) which belongs to a family of well studied three-fingered neurotoxins.
@@ Line 32: / Line 32: @@
-Denmotoxin is a monomeric protein comprising of 77 amino acid residues. Denmotoxin consists of <scene name='57/579702/Three_fingers/1'>three polypeptide loops</scene> protruding from the <scene name='57/579702/3ftx_beta_strands/2'>globular core</scene>; this structure is typical for 3FTXs. The globular core consists of a  triple stranded anti-parallel β-sheet  ; two of the β-strands in this structure connect to the second loop (central loop) and one β-strand connects to the third loop. There are two highly <scene name='57/579702/Flexible_regions/2'>flexible regions</scene> on the protein: one at the tip of the central loop and one at the 3 first residues of the N-terminus; the expected active site of denmotoxin is at the tip of the central loop.
+Denmotoxin is a monomeric protein comprising of 77 amino acid residues. Denmotoxin consists of <scene name='57/579702/Three_fingers/1'>three polypeptide loops</scene> (fig. 2) protruding from the <scene name='57/579702/3ftx_beta_strands/2'>globular core</scene>; this structure is typical for 3FTXs. The globular core consists of a  triple stranded anti-parallel β-sheet  ; two of the β-strands in this structure connect to the second loop (central loop) and one β-strand connects to the third loop. There are two highly <scene name='57/579702/Flexible_regions/2'>flexible regions</scene> on the protein: one at the tip of the central loop and one at the 3 first residues of the N-terminus; the expected active site of denmotoxin is at the tip of the central loop.
 There are 10 structurally important cysteine-residues in denmotoxin which form five stabilizing <scene name='57/579702/Disulphides/3'>disulphide bonds</scene>. Four of these disulphide bonds, which are found in all 3FTXs are located at the central core and the fifth additional bond is found at the tip of the first loop. The cysteine residues of all 3FTXs are highly conserved, whereas the other residues within the sequence express high variability. Denmotoxin possesses most of the conserved residues invariant among 3FTXs which have been shown to be important for the proper folding of and structure of protein. The presence of these structurally important residues result in the characteristic three finger fold of the toxin (e.g. Gly52, Pro58).
@@ Line 43: / Line 43: @@
-[[Image:Bungarotoxin interaction with nACHr figure text.png‎|300px|right|thumb| Suggested interaction of '''α-bungarotoxin''' in binding pocket of nAChR (simplified figure) [PDB=4HQP]]]
+[[Image:Bungarotoxin interaction with nACHr figure text.png‎|300px|right|thumb| Figure 3. Suggested interaction of '''α-bungarotoxin''' in binding pocket of nAChR (simplified figure) [PDB=4HQP]]]
-Most of the 3FTX family proteins possess a highly conserved arginine in the tip of their binding loop responsible for interaction with nAChRs. This interaction was determined by resolving a structure of α7 nAChR chimera in a complex with α-bungarotoxin (see fig.). In denmotoxin, this loop contains several changes in its sequence; arginine has replaced by aspartic acid (ASP41) and two additional glutamates (GLU42 & GLU45) generate untypical <scene name='57/579702/Negative_charge/1'>negative charge</scene> into the loop.
+Most of the 3FTX family proteins possess a highly conserved arginine in the tip of their binding loop responsible for interaction with nAChRs. This interaction was determined by resolving a structure of α7 nAChR chimera in a complex with α-bungarotoxin (fig. 3). In denmotoxin, this loop contains several changes in its sequence; arginine has replaced by aspartic acid (ASP41) and two additional glutamates (GLU42 & GLU45) generate untypical <scene name='57/579702/Negative_charge/1'>negative charge</scene> into the loop.
 Biochemistry of denmotoxin is unique for its taxon specificity to bird nicotinic acetylcholine receptors (nAChR). Binding of denmotoxin to chick muscle AChR (α1βγδ) is a highly irreversible whereas interaction with identical subunit assembly in mouse AChR is reversible. The reversible binding allows the receptor to function properly, but in the case of irreversible binding nAChR is prevented of natural agonist activation. Previous studies <ref>Samson. A. O. & Levitt M., [http://pubs.acs.org/doi/abs/10.1021/bi702272j "Inhibition Mechanism of the Acetylcholine Receptor by α-Neurotoxins as Revealed by Normal-Mode Dynamics"], ''Biochemistry, 2008, 47 (13), pp 4065–4070'', March 8, 2008. Retrieved May 19, 2014.</ref> with 3FTXs have shown that the binding of toxin leads to “locking down” of the nACh receptor, preventing required conformational change for ion channel activation and induction of signal.