Sandbox GGC13

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Crystal Structure of Lactate Dehydrogenase A in complex with the inhibitor, oxamate.
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==1BVN: Pig Pancreatic Alpha-Amylase==
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<StructureSection load='1I10' size='340' side='right' caption='Crystal Structure L-Lactate Dehydrogenase A interacting with inhibitor, Oxamate' scene=''>
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<StructureSection load='1BVN' size='340' side='right' caption='Caption for this structure' scene=''>
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This protein that is being explained is commonly known as the Pig Pancreatic Alpha-Amylase that is in complex with the proteinaceous inhibitor tendamistat.
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Lactate dehydrogenase is a ubiquitous protein found throughout nearly all living organisms. Primarily it is involved in the final step of glycolysis, the fermentation of pyruvate to lactate while recycling a reduced form of NADH. The regulation of LDH's activity is sought after due to the displayed relationship between activity and cancer cell proliferation. <ref>DOI 10.1126/science.1160809</ref>
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== Function ==
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The function of the protein that is listed on the uniport website states that the two forms of this enzyme show that it is very similar with its activities, molecular masses, and compositions to each other but show differences in their isoelectric points only. There is no evidence of that the two variants in the cDNA library on PubMed: 10082956. The two forms, isoform I (PPAI) and isoform II (PPAII), are most likely the same protein. There is endohydrolysis of (1-4)-alpha-D-glucosidic linkages in the polysaccharides that contain three or more (1-4)-alpha-linked-D-glucose units.
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== Function ==
 
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Lactate Dehydrogenase(LDH) is a large, two domain- protein which catalyzes the conversion of pyruvate to lactate under anaerobic conditions.<ref>DOI 10.1126/science.1160809</ref> This conversion is coupled with the reduction of NAD+ to form the electron carrying NADH. Muscular LDH is involved in the Cori Cycle where it transports newly synthesized lactate to the liver. Liver LDH converts the lactate back to pyruvate in order to provide the precursor for gluconeogenesis.<ref>DOI 10.1126/science.136.3520.962</ref>
 
== Disease ==
== Disease ==
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Lactate dehydrogenase is found in its various isoenzyme forms throughout the body, including: brain, red blood cells, lungs, kidney, placenta, pancreas, muscle, and liver. It is kept at relatively low concentrations and is only utilized as a pathway under anaerobic conditions as it produces less ATP/glucose than oxidative phosphorylation. High levels of LDH are generally indicative of poor health. LDH translation is found to be overly expressed in pancreatic cancer and showed correlation with cell growth success rate. <ref>DOI 10.1126/science.1160809</ref> <ref>10.1007/s13277-013-0679-1</ref>
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This protein is not associated with any diseases at this time.
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Increased LDH levels are also associated with conditions such as Rhabdomyolysis which is characterized by the breakdown of skeletal muscle. This is due in part to LDH in red blood cells being released through hemolysis.
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Conversely, LDH deficiency is also indicative of health problems. Decreased levels of LDH can lead to metabolic muscle disorders which have a number of symptoms and complications. The most serious of these being myoglobinuria and Rhabdomyolysis.
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== Relevance ==
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((need to research relevance of the protein))
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==Structure==
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There is the processing of the protein in the single peptide with the location of 1-15 and the chain with the location of 16-511. The modifications of the protein can be found in the modified residue (16), disulfide bonds (43-101, 85-130, 156-175, 393-399,465-477), and glycosylation (427). There is no active site on this protein.
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The protein is located in the extracellular region of the cell or secreted.
== Structural highlights ==
== Structural highlights ==
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Lactate dehydrogenase is a tetramer protein which can form five different isoenzymes.<ref>DOI 10.1126/science.136.3520.962</ref> Subunits exist primarily in two isoforms: M and H, which differ in a single residue. The M subunit contains an alanine while the H subunit contains a glutamine.<ref>PMID: 197516</ref> The combination of subunits defines which isoenzyme is formed and indicates where the enzyme will be present in the body. Lactate dehydrogenase A is composed of four M subunits. The subunits can adopt two conformations, open and closed, which determine the subunits activity. <ref>DOI 10.3390/molecules22122217</ref>
 
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The active site contains three different binding pockets to accommodate the substrate, Nicotinamide, and adenine.
 
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The substrate binding pocket relies on heavily on hydrogen binding and ionic interactions in order to effectively bind the substrate. Upon binding, the substrate binding pocket undergoes a conformational change where interactions between the substrate or inhibitor and a glutamine residue (Q99) essentially pull the active loop closed. <ref>DOI 10.3390/molecules22122217</ref>
 
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<scene name='78/781197/Oxamate/4'>Close up interactions between the substrate binding pocket and the inhibitor, oxamate. The substrate active site to which oxamate is bound is in the closed conformation.</scene>
 
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The nicotinamide and adenine binding pockets work together to successfully bind NADH. Both binding pockets implement hydrogen bonding and hydrophobic interactions with their ligand fragment. In addition to the interactions within the binding pockets, NADH is also supported by ionic forces between arginine (R99) and the pyrophosphate groups. <ref>DOI 10.3390/molecules22122217</ref>
 
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<scene name='78/781197/Nadh/3'>Close up interactions between the NADH and adenine binding pockets and the cofactor, NADH.</scene>
 
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The hydroxyl groups of NADH's ribose fragments interacts with the H-bond network created by the substrate and asparagine (N137). <ref>DOI 10.3390/molecules22122217</ref>
 
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<scene name='78/781197/Oxamate_and_nadh/1'>Simplified wireframe model displaying the inhibitor-NADH Hydrogen bond network involving asparagine.</scene>
 
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
</StructureSection>
</StructureSection>
== References ==
== References ==
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<ref>DOI 10.3390/molecules22122217</ref>
 
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<ref>DOI 10.1126/science.1160809</ref>
 
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<ref>10.1007/s13277-013-0679-1</ref>
 
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<ref>PMID 197516</ref>
 
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<ref>DOI 10.1126/science.136.3520.962</ref>
 
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<ref>DOI 10.1002/mus.880181413</ref>
 
<references/>
<references/>

Current revision

1BVN: Pig Pancreatic Alpha-Amylase

Caption for this structure

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References

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