Sandbox Reserved 191: Difference between revisions
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===Mutations leading to Infantile Neuronal Ceroid Lipofuscinosis=== | ===Mutations leading to Infantile Neuronal Ceroid Lipofuscinosis=== | ||
Various mutations have been found in INCL patients<ref name="Ryan-1">PMID:10191107</ref>. Most of these mutations are caused by nonsense or missense mutations within close proximity to the catalytic <scene name='43/436866/Triad_w_zoom_no_backbones/1'>triad</scene>. These mutations lead to an inactive PPT-1 enzyme as they are predicted to create unfavorable steric, polar, and electrostatic interactions that could disturb the nucleophilic elbow <ref name="mutations" />. The nucleophilic elbow is responsible for proper location and orientation of the Ser-115. The catalytic activity of PPT-1 is greatly reduced if the positioning of Ser-115 is altered, as Ser-115 must be properly orientated to be activated by His-289 to be positioned to attack the substrate. An example of a INCL mutation such as <scene name='58/580837/Methionine/9'>Val181Met</scene> and <scene name='58/580837/Lysine_mutation/4'>Glu184Lys</scene> gives a good depiction of how the increase in size in the mutated amino acids and positive charge on the inserted lysine residue would create steric and polar clashes with the adjacent helices of the binding pocket compared to the <scene name='58/580837/Val181glu184/3'> | Various mutations have been found in INCL patients<ref name="Ryan-1">PMID:10191107</ref>. Most of these mutations are caused by nonsense or missense mutations within close proximity to the catalytic <scene name='43/436866/Triad_w_zoom_no_backbones/1'>triad</scene>. These mutations lead to an inactive PPT-1 enzyme as they are predicted to create unfavorable steric, polar, and electrostatic interactions that could disturb the nucleophilic elbow <ref name="mutations" />. The nucleophilic elbow is responsible for proper location and orientation of the Ser-115. The catalytic activity of PPT-1 is greatly reduced if the positioning of Ser-115 is altered, as Ser-115 must be properly orientated to be activated by His-289 to be positioned to attack the substrate. An example of a INCL mutation such as <scene name='58/580837/Methionine/9'>Val181Met</scene> and <scene name='58/580837/Lysine_mutation/4'>Glu184Lys</scene> gives a good depiction of how the increase in size in the mutated amino acids and positive charge on the inserted lysine residue would create steric and polar clashes with the adjacent helices of the binding pocket compared to the <scene name='58/580837/Val181glu184/3'>normal Val-181 and Glu-184</scene>. <scene name='58/580837/Arginine_fine/5'>normal Arg-122</scene> which is below <ref name="Ryan-1">PMID:10191107</ref>. | ||
(*All mutation scenes are the proposed best rotamers of the mutation. These mutations were created through the use of the mutagenesis wizard in the PyMOL program) | (*All mutation scenes are the proposed best rotamers of the mutation. These mutations were created through the use of the mutagenesis wizard in the PyMOL program) | ||