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| - | =='''Alpha- Crystallin AB Chain'''== | + | ==5CEQ DLK in complex with inhibitor 50F (2-((1-cyclopentyl-5-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-3-yl)amino)isonicotinonitrile)== |
| - | <StructureSection load='2KRL' size='340' side='right' caption='Caption for this structure' scene=''> | + | <StructureSection load='5ceq' size='340' side='right'caption='[[5ceq]], [[Resolution|resolution]] 1.91Å' scene=''> |
| - | Alpha Crystallin a hetero-oligameric complex with a size of about 700 to 800 kDa. <ref>PMID:15570221</ref> Alpha A and Alpha B Crystallin are proteins that encoded by the genes CRYAA and CRYAB. Alpha A and B are a major protein component of the mammalian eye lens that makes up about 40% of the eye lens protein. Alpha A crystallin is mainly found on the lens of the eye with trace amounts in other tissues while Alpha B is essentially considered a ubiquitous protein. <ref name= "alpha">PMID:12565801</ref> Alpha Crystallin is part of the small heat- shock protein family that has a conserved homologous sequence of 90 to 100 residues <ref>PMID: 8450753</ref>
| + | 5CEQ is a MAP3K12 protein from homo sapiens. It plays a role in the MAPK Cascade pathway mostly by interacting with the JNKs, SAPKs, and ERKs which are part of part of the MAP kinases. Since some of the MAP kinases are involved with the central nervous system signaling, it has been shown that DLK also plays a role in protection of neurons when inhibited by 50F. |
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| | == Function == | | == Function == |
| - | This protein contributes to the transparency and refractive index of the eye lens. Alpha- Crystallin can act as chaperones preventing the aggregation of various proteins. Even though they act as molecular chaperones, they don't renature proteins and release them like true chaperones do; instead, they hold proteins in large soluble aggregates. <ref>PMID:2255369</ref> It's chaperone properties gives the ability to prevent aggregation of denatured proteins and increase stress tolerance for cell. <ref>PMID:15575808</ref> Also, it has been shown that Alpha B chain is involved in the inhibition of apoptosis <ref>PMID:24725344</ref>
| + | Regulates JNK/SAPK cascade, transferase phosphorylation |
| | == Disease == | | == Disease == |
| - | '''Cataracts 9, multiple types'''
| + | Neuron degenerative diseases such as Parkinson’s, and Alzheimer. |
| | + | == Relevance == |
| | + | This protein will help us understand more about the physiology of degenerative diseases, which will lead to making more medicine that could possibly slow the deterioration process, or even cure the diseases. |
| | + | == Structural highlights == |
| | + | <scene name='78/781195/00ligand/1'>50F</scene> |
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| - | This disease is caused by mutations affecting the eye lens. One of those mutations is usually R116C where an arginine is mutated to a cysteine. R116C is generally linked to one form of autosomal congenital cataracts. Congenital cataracts refers to the opacification of the eye lens that occurs at birth while infantile cataracts refers to the opacification of eye lens that developed during the first year. <ref>PMID:26319346</ref> An opacification of the crystalline lens of the eye occurs, in most instances, may lead to impairment or blindness. Opacities vary in morphology it might be static or progressive. <ref>PMID:11123904</ref>
| + | <scene name='78/781195/01dfg_active_site/1'>active site</scene> |
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| - | '''Myopathy, Miofibrillar''' | + | <scene name='78/781195/03asp161/1'>ASP161</scene> |
| - | A group of chronic neuromuscular disorder characterized by the disintegration of the sarcomere Z disc and myofibrils. Myopathy is characterized by weakness of proximal and distal limbs, weakness of neck, hypertrophy cardiomyopathy, and cataracts in a subset of patients. <ref>PMID:14681890</ref>
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| - | '''Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin''' | + | |
| - | This is another form of myopathy myofibril, but it happens in infants. It is a chronic neuromuscular disorder characterized by disintegration of sarcomere Z disc and myofibrils. MFMFIH-CRYAB has onset on the first weeks of life after the neonatal period. Affected infants show rapid muscular rigidity of trunks and limbs which is associated with increasing respiratory difficulties resulting in death before the age of 3. <ref>PMID:21337604</ref>
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| | | | |
| - | '''Dilated Cardiomyopathy'''
| + | </StructureSection> |
| - | DCM is known to be caused by mutations sarcomere proteins including alpha crystallin b and titin also known as connectin. It's a condition where the heart muscle is enlarged and weakened. DCM is characterized by the dilation of ventricles accompanied by systolic dysfunction which can result in heart failure and arrhythmias. Alpha crystallin b is associated with this disease because a missense mutation of R157H was found in familial DCM. <ref>PMID:16483541</ref>
| + | Gene: MAP3K12 |
| | | | |
| - | == Relevance ==
| + | Related proteins: 5CEO, 5CEN, Q12852 |
| - | Alpha Crystallin A 1-172 is found at nearly 2 folds higher in diabetic lenses than an aged matched control lens. In humans, the alpha A gene is found in chromosome 21 and encodes for 173 amino acid residues while the alpha B gene is found in chromosome 11 and encodes for 175 amino acids.<ref name="alpha" /> In mammalian lens, the molar ratio between alpha A and alpha B is a 3 to 1 ratio. <ref>PMID:20836128</ref>
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| - | An increased level of Alpha Crystallin B chain has been associated with various diseases such Alexander's disease, Alzheimer's, and Parkinson's. <ref>PMID:8256860</ref>
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| | | | |
| - | == Structural highlights ==
| + | Ligand: 50F |
| | | | |
| | + | == References == |
| | + | 1. Patel S, Harris SF, Gibbons P, Deshmukh G, Gustafson A, Kellar T, Lin H, Liu X, Liu Y, Liu Y, Ma C, Scearce-Levie K, Ghosh AS, Shin YG, Solanoy H, Wang J, Wang B, Yin J, Siu M, Lewcock JW. Scaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant N-(1H-Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12). J Med Chem. 2015 Oct 2. PMID:26431428 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01072 |
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| - | This structure highlight shows where <scene name='78/781195/2klrarg_116/2'>Arg 116</scene> is located in the A chain. A mutation of this amino acid to cysteine will lead to cataracts. <ref name="alpha" />
| + | 2. Cargnello, M., & Roux, P. P. (2011). Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiology and molecular biology reviews : MMBR, 75(1), 50–83. https://doi.org/10.1128/MMBR.00031-10 |
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| - | The following structure shows where <scene name='78/781195/Arginine120b/3'>Arg 120 on B chain</scene> is located. The mutation of this amino acid in the B chain of crystalline gene decreased interaction with wild-type CRYAA and CRYAB. However, it increases interactions with CRBB2 and CRYGC leading to cytoplasmic aggregation. <ref>PMID:12601044</ref> Also, when Arg is mutated to Gly, it causes desmin- related myopathy, cardiomyopathy, and cataracts. Also, this mutation reduces chaperone protection activity and in some target proteins promoted aggregation. <ref name="alpha" />
| + | 3. Siu M, Sengupta Ghosh A, Lewcock JW. Dual Leucine Zipper Kinase Inhibitors for the Treatment of Neurodegeneration. J Med Chem. 2018 Sep 27;61(18):8078-8087. doi: 10.1021/acs.jmedchem.8b00370. Epub 2018 Jun 4. PMID: 29863360. |
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| - | This highlight shows the location of the <scene name='78/781195/His_abr/2'>Histidine amino acids</scene> involved in inter-subunit bridging of Zn2+ ions which enhances stability.<ref>PMID:22890888</ref> This is crucial as there is no protein turnover in the lens.
| + | 4. Patel S, Cohen F, Dean BJ, De La Torre K, Deshmukh G, Estrada AA, Ghosh AS, Gibbons P, Gustafson A, Huestis MP, Le Pichon CE, Lin H, Liu W, Liu X, Liu Y, Ly CQ, Lyssikatos JP, Ma C, Scearce-Levie K, Shin YG, Solanoy H, Stark KL, Wang J, Wang B, Zhao X, Lewcock JW, Siu M. Discovery of dual leucine zipper kinase (DLK, MAP3K12) inhibitors with activity in neurodegeneration models. J Med Chem. 2015 Jan 8;58(1):401-18. doi: 10.1021/jm5013984. Epub 2014 Oct 23. PMID: 25341110./> |
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| - | This structure shows <scene name='78/781195/Lys72/2'>Lys 72</scene>. When this amino acid is acetylated, there might be an increase the chaperone activity for the protein. Chaperon activity is highly necessary because it plays a critical role in maintaining lens transparency. <ref>PMID:22120592</ref>
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| - | This structure highlights <scene name='78/781195/Asp/1'>Asp 109</scene>. A mutation of asp 109 to his is associated with restrictive cardiomyopathy and aggregation of CRYAB and DES gene. This mutation reduces the localization of Desmin and alpha crystallin b in the Z band and intercalated disc of the myocardium. <ref>PMID: 28493373</ref>. Also, when asp 109 is mutated to his is associated with myofibrillar myopathy and polar cataracts. <ref>PMID: 21920752</ref>
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| - | | + | |
| - | The following structure shows <scene name='78/781195/Crystallin/1'>Alpha Crystallin Structure</scene> with all the chains that make it up.
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| - | | + | |
| - | </StructureSection>
| + | |
| - | == References ==
| + | |
| - | <references/>
| + | |
1. Patel S, Harris SF, Gibbons P, Deshmukh G, Gustafson A, Kellar T, Lin H, Liu X, Liu Y, Liu Y, Ma C, Scearce-Levie K, Ghosh AS, Shin YG, Solanoy H, Wang J, Wang B, Yin J, Siu M, Lewcock JW. Scaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant N-(1H-Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12). J Med Chem. 2015 Oct 2. PMID:26431428 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01072
2. Cargnello, M., & Roux, P. P. (2011). Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiology and molecular biology reviews : MMBR, 75(1), 50–83. https://doi.org/10.1128/MMBR.00031-10
3. Siu M, Sengupta Ghosh A, Lewcock JW. Dual Leucine Zipper Kinase Inhibitors for the Treatment of Neurodegeneration. J Med Chem. 2018 Sep 27;61(18):8078-8087. doi: 10.1021/acs.jmedchem.8b00370. Epub 2018 Jun 4. PMID: 29863360.
4. Patel S, Cohen F, Dean BJ, De La Torre K, Deshmukh G, Estrada AA, Ghosh AS, Gibbons P, Gustafson A, Huestis MP, Le Pichon CE, Lin H, Liu W, Liu X, Liu Y, Ly CQ, Lyssikatos JP, Ma C, Scearce-Levie K, Shin YG, Solanoy H, Stark KL, Wang J, Wang B, Zhao X, Lewcock JW, Siu M. Discovery of dual leucine zipper kinase (DLK, MAP3K12) inhibitors with activity in neurodegeneration models. J Med Chem. 2015 Jan 8;58(1):401-18. doi: 10.1021/jm5013984. Epub 2014 Oct 23. PMID: 25341110./>
