Sandbox GGC5

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=='''Titin'''==
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=='''Beta Lactamase'''==
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<StructureSection load='1TIT' size='340' side='right' caption='Caption for this structure' scene=''>
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<StructureSection load='3ZWF' size='340' side='right' caption='tRNAse Z Metallo-Beta Lactamase (homosapien)' scene=''>
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Titin,one of the largest human protein, in its longest isoform, has a molecular weight exceeding 3 MDa and is over 1.5 μm in length. Titin typically contains immunoglobulin (Ig) domains which are typically 110 amino acids in length, contain an internal disulfide bond and two layers of β-pleated sheets.<ref>PMID:31856237</ref> On the cellular level, titin is typically located within the nucleus of the cell; however, it can also be located within the cytoplasm. <ref>DOI 10.1002/ijch.201300024</ref>
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== '''Function''' ==
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Beta Lactamase is a highly conserved enzyme in both prokaryotes and eukaryotes. In prokaryotes, it gives bacteria such as ''E.coli'' antibiotic resistance. In eukaryotes, it acts as exo and endonucleases to regulate transcription activity.
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Titin is a key component in the assembly and function of vertebrate striated muscles. Titin provides connections at the level of individual micro-filaments and contributes to the fine balance of forces between the two halves of the sarcomere.
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Titin plays a vital role in the highly ordered macromolecular complex of the sarcomere structures and functions requiring the controlled integration of striated myofibrils in differentiating myocytes. The giant titin protein extends over on half of the sarcomeric unit.
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In non-muscle cells, titin plays a role in chromosome condensation and chromosome segregation during mitosis.
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=='''Background Information'''==
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There are several classes of antibiotics, including cephalosporin and penicillin <ref>doi: 10.1016/j.jmb.2019.04.002</ref>. Some common examples of specific drugs in these classes include cefazolin, cefadroxil, penicillin, ampicillin, and methicillin <ref>doi: 10.1016/j.jmb.2019.04.002</ref>. These antibiotics function by preventing bacteria from forming their cell wall, regardless if the bacteria are gram positive or gram negative <ref>doi: 10.1016/j.jmb.2019.04.002</ref>. These antibiotics all contain a beta-lactam ring <ref>https://doi.org/10.1021/cr030102i</ref>.
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Inside of the gram positive or gram negative bacteria, there is a protein called the penicillin binding protein. The penicillin binding proteins (PBPs) are what help the peptidoglycan walls to form by linking NAG and NAM chains together. The beta-lactam ring fits particularly well into the PBP, which is how antibiotics like penicillin prevent bacteria from synthesizing its cell wall.
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Protein kinase, including titin kinase, is a vital aspect of controlling cell proliferation and cell differentiation. Titin kinase is expressed in muscles and is responsible for the interaction with thick filaments known as myosin filaments. The enzymatic activity of protein kinases must be highly regulated through the phosphorylation of specific residues located in the activation component of the catalytic domain. Titin kinase is regulated in a two-step process including the partial unfolding of an inhibitory segment to expose the catalytic region followed by the phosphorylation of the Tyrosin residue. This tyrosine residue is depicted in the structural highlights listed below. <ref>PMID:19108772</ref>,<ref name="tyr">PMID:9804419</ref>
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[[Image:beta lactam ring in antibiotics.png]]
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Beta Lactam Ring present in Antibiotics
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== '''Disease''' ==
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[[Image:Penicillin inhibition.svg]]
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'''Myopathy, myofibrillar, 9, with early respiratory failure:'''
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Penicillin inhibition
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This disease is characterized by adult onset of weakness in proximal (shoulder, upper arm, pelvic area and thighs), distal (lower arms/legs, hands and feet), axial (trunk and head) and respiratory muscles. The main symptoms of onset are pelvic girdle and neck weakness. Ultimately, the weakness will affect the proximal compartment of both the upper and lower limbs. Additional symptoms include varying degrees of Achilles tendon contractures, spinal rigidity and muscle hypertrophy. In extreme cases, respiratory involvement will often lead to the requirement for non-invasive treatment. The natural variant indicating this disease can be found at position 279 and it disrupts NBR1-binding. <ref>PMID:15802564</ref>
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=='''Mechanism of Antibiotic Beta Lactam Ring Resistance'''==
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Bacteria such as ''E. coli'' make and excrete an enzyme called beta lactamase <ref>DOI: 10.1080/10409230701279118</ref>. Bacteria can become resistant to antibiotics that contain lactam rings when the B-lactamase enzyme attacks the beta lactam ring (classified as a hydrolase). Once the beta lactam ring is sliced open, it is no longer functional <ref> DOI 10.2210/pdb3ZWF/pdb </ref>.
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=='''Beta Lactamase in Humans (PDB: 3ZWF)'''==
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'''Cardiomyopathy, familial hypertrophic 9:'''
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In order to make mature tRNAs, first they have to be processed <ref>https://doi.org/10.1101/575373</ref>. The enzyme that does tRNA processing is called TRNase Z. In humans, the form of beta lactamase formed uses a zinc-dependent mechanism, noted as metallo-beta lactamase <ref>DOI: 10.1080/10409230701279118</ref>. These enzymes in humans function to regulate nuclear activity, providing exo and endonuclease activity.
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This disease is a hereditary heart disorder characterized by ventricular hypertrophy. The hypertrophy is usually asymmetrical and often involves the interventricular septum (lower heart chambers). The symptoms of this disease include: difficult/labored breathing, fainting, collapse, palpitations and chest pains. These symptoms are often directly agitated by exercise or exertion. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms. Ultimately, this disease has a high risk of cardiac failure and sudden cardiac death. This disease is characterized by a variant in position 740. <ref name="cardio">PMID:10462489</ref>
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=='''Structural highlights'''==
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'''Cardiomyopathy, dilated 1G:'''
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Macromolecules:
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Two chains (A,B) of Zinc phosphodiesterase ELAC Protein 1 <ref>DOI 10.2210/pdb3ZWF/pdb</ref>.
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This disorder is characterized by ventricular dilation and impaired systolic function. This disorder results in congestive heart failure and arrhythmia, ultimately leading to a high possibility of premature death. This disease is often indicated by natural variants in the following locations: 54, 743, 976, 3799, 4465 or 32996. All of these variants affect the interaction with the TCAP/telethonin. <ref>PMID:11846417</ref>
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''Unique Ligands''
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'''Tardive tibial muscular dystrophy:'''
 
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This disease is a late-onset, autosomal dominant distal myopathy. Symptoms are typically muscle weakness and atrophy that are typically confined to the anterior compartment of the lower leg. Clinical onset of this disease usually occur at 35 to 45 years or later. The natural variant of this disease occurs at positions 34306 and 34315. <ref name="dyst">PMID:12145747</ref>
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- Phosphate (PO4) ligand on chains A and B of Zinc phosphodiesterase ELAC Protein 1 <ref>DOI 10.2210/pdb3ZWF/pdb</ref>.
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'''Muscular dystrophy, limb-girdle, autosomal recessive 10:'''
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<scene name='78/781193/Po4/1'>PO4 Ligand</scene>
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This disease is characterized by progressive weakness of the pelvic and shoulder girdle muscles. Muscular dystrophy is an autosomal recessive denerative myopathy that results in severe disability observed within 20 years of its onset. <ref name="dyst" />
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- Zinc (Zn) ligand on chains A and B of Zinc phosphodiesterase ELAC Protein 1 <ref>DOI 10.2210/pdb3ZWF/pdb</ref>.
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'''Salih myopathy:'''
 
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This myyopathy is an autosomal recessive, early-onset muscular disorder. This disease is characterized by dilated cardiomyopathy, delayed motor development with generalized muscle weakness predominantly affecting proximal and distal lower limbs. Minicore-like lesions with mitochondrial depletion and sarcomere disorganization and cenralized nuclei are present in the skeletal muscle biopsies of affected individuals. Cardiac muscle biopsies display a disruption of myocardial architecture, nuclear hypertrophy, and endomysial fibrosis. This disease can result in sudden death. Mutagenesis occurs in positions 32207 and 32341 and disrupts catalytic activity. <ref>PMID:17444505</ref>
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<scene name='78/781193/2_zincs/1'>Zinc ions are adjacent to the phosphate to balance the charge</scene>
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== '''Relevance''' ==
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- 2007 hydrophobic amino acid residues <ref>DOI 10.2210/pdb3ZWF/pdb</ref>.
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[[Image:Titin.JPG]]
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<scene name='78/781193/Hydrophobic_amino_acids/1'>hydrophobic amino acid properties </scene>
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'''This figure illustrates the ability of titin to coil and extend during muscle contraction and extension.'''<ref name="figure">PMID:10895161</ref>
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- 1878 polar amino acid residues <ref>DOI 10.2210/pdb3ZWF/pdb</ref>.
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<scene name='78/781193/Polar_amino_acids/1'>polar amino acids</scene>
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Titin is a flexible filament containing a beaded substructure indicating the presence of multiple domains within the molecule. These multiple domains include: the immunoglobulin domain, the Fibronectin type-II domain, the PEVK (proline-glutamate-valine-lysine-enriched unique sequence region, the unique sequences and the kinase domain. <ref name="figure" />
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== '''Structural highlights''' ==
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•This is the <scene name='78/781193/Titin_rainbow_tc/1'>rainbow</scene> version of the titin molecule. This structure is colored to differentiate each chain, starting with the blue 5' amino end, ending with the red 3' carboxyl end.
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- Sodium (Na+) ion on chain B of Zinc phosphodiesterase ELAC Protein 1 <ref>DOI 10.2210/pdb3ZWF/pdb</ref>.
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<scene name='78/781193/Sodium_ion_enlarged/1'>Sodium Ion present</scene>
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•This secondary structure of titin highlights the <scene name='78/781193/Hydrophobic_structure_tc_trp/1'>Polar sections</scene> of the titin molecule. In this representation, Polar sections of titin are shaded in purple and hydrophobic regions are shaded in grey. The central beta-sandwich structure of the molecule encloses a well defined hydrophobic core. This helps to stabilize the molecule that contains no disulfide bridges and rely solely on hydrogen bonding in the side chains and backbone. Trp34 is also highlighted in this representation to display the central position of the elongated hydrophobic core formed between the two β sheets of the classical Ig folded domain. <ref>PMID:8805538</ref>
 
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•This alternate structure highlights the <scene name='78/781193/Tyr_selection_tc/1'>Tyrosine</scene> involved in activity regulation. Full activation of the protein kinase domain requires both phosphorylation of Tyrosine to prevent it from blocking the catalytic aspartate residue, and binding of the C-terminal regulatory tail of the molecule which results in ATP binding to the kinase. <ref name="tyr" />
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</StructureSection>
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•This structure view highlights the <scene name='78/781193/Titin_mutation_tc_val/2'>VAL residue 54</scene>.The VAL residue located at #54 is one of the mutations present in the cardiomyopathy,familial hypertrophic 9, disease. This VAL residue is replaced by a MET residue when the disease is present in an infected individual. <ref name="cardio" />
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=='''Disease'''==
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If there are mutations in the tRNase Z metallo-beta lactamases, these enzymes have been implicated in several diseases including prostate cancer <ref>DOI: 10.1080/10409230701279118</ref>. While there is still much to learn about how these lactamases work inter-connectedly with other enzymes, research suggests that metallo-beta lactamases function as cleavage and polyadenylation factors <ref>https://doi.org/10.1101/575373</ref>.
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•This is the <scene name='78/781193/Complete_structure_tc/1'>complete titin</scene> structure. This secondary view shows multiple titin proteins connected together. This representation is known as the titin band.
 
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•These are the <scene name='78/781193/Titin_pro_tc/1'>Proline residues</scene> located in the PEVK domain that is vital to the elasticity characteristics of titin.<ref name="figure" />
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== '''Evolutionary Considerations''' ==
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Beta Lactamase protein structure is highly conserved across both prokaryotes and eukaryotes <ref>doi: https://doi.org/10.1101/819797</ref>. Their presence indicates that these proteins are highly adaptable, with a wide range of substrates <ref>https://doi.org/10.1101/575373</ref>. The highly conserved nature of this structure suggests that the genetic material for beta lactamase is ancient in origin <ref>https://doi.org/10.1101/575373</ref>. They have found early beta lactamases in deep sea sediment, before the first antibiotic was ever encountered.
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</StructureSection>
 
== '''References''' ==
== '''References''' ==
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Current revision

Contents

Beta Lactamase

tRNAse Z Metallo-Beta Lactamase (homosapien)

Drag the structure with the mouse to rotate

Disease

If there are mutations in the tRNase Z metallo-beta lactamases, these enzymes have been implicated in several diseases including prostate cancer [15]. While there is still much to learn about how these lactamases work inter-connectedly with other enzymes, research suggests that metallo-beta lactamases function as cleavage and polyadenylation factors [16].


Evolutionary Considerations

Beta Lactamase protein structure is highly conserved across both prokaryotes and eukaryotes [17]. Their presence indicates that these proteins are highly adaptable, with a wide range of substrates [18]. The highly conserved nature of this structure suggests that the genetic material for beta lactamase is ancient in origin [19]. They have found early beta lactamases in deep sea sediment, before the first antibiotic was ever encountered.


References

  1. ↑ Tooke CL, Hinchliffe P, Bragginton EC, Colenso CK, Hirvonen VHA, Takebayashi Y, Spencer J. beta-Lactamases and beta-Lactamase Inhibitors in the 21st Century. J Mol Biol. 2019 Aug 23;431(18):3472-3500. doi: 10.1016/j.jmb.2019.04.002. Epub, 2019 Apr 5. PMID:30959050 doi:http://dx.doi.org/10.1016/j.jmb.2019.04.002
  2. ↑ Tooke CL, Hinchliffe P, Bragginton EC, Colenso CK, Hirvonen VHA, Takebayashi Y, Spencer J. beta-Lactamases and beta-Lactamase Inhibitors in the 21st Century. J Mol Biol. 2019 Aug 23;431(18):3472-3500. doi: 10.1016/j.jmb.2019.04.002. Epub, 2019 Apr 5. PMID:30959050 doi:http://dx.doi.org/10.1016/j.jmb.2019.04.002
  3. ↑ Tooke CL, Hinchliffe P, Bragginton EC, Colenso CK, Hirvonen VHA, Takebayashi Y, Spencer J. beta-Lactamases and beta-Lactamase Inhibitors in the 21st Century. J Mol Biol. 2019 Aug 23;431(18):3472-3500. doi: 10.1016/j.jmb.2019.04.002. Epub, 2019 Apr 5. PMID:30959050 doi:http://dx.doi.org/10.1016/j.jmb.2019.04.002
  4. ↑ https://doi.org/10.1021/cr030102i
  5. ↑ Dominski Z. Nucleases of the metallo-beta-lactamase family and their role in DNA and RNA metabolism. Crit Rev Biochem Mol Biol. 2007 Mar-Apr;42(2):67-93. doi:, 10.1080/10409230701279118. PMID:17453916 doi:http://dx.doi.org/10.1080/10409230701279118
  6. ↑ doi: https://dx.doi.org/10.2210/pdb3ZWF/pdb
  7. ↑ https://doi.org/10.1101/575373
  8. ↑ Dominski Z. Nucleases of the metallo-beta-lactamase family and their role in DNA and RNA metabolism. Crit Rev Biochem Mol Biol. 2007 Mar-Apr;42(2):67-93. doi:, 10.1080/10409230701279118. PMID:17453916 doi:http://dx.doi.org/10.1080/10409230701279118
  9. ↑ doi: https://dx.doi.org/10.2210/pdb3ZWF/pdb
  10. ↑ doi: https://dx.doi.org/10.2210/pdb3ZWF/pdb
  11. ↑ doi: https://dx.doi.org/10.2210/pdb3ZWF/pdb
  12. ↑ doi: https://dx.doi.org/10.2210/pdb3ZWF/pdb
  13. ↑ doi: https://dx.doi.org/10.2210/pdb3ZWF/pdb
  14. ↑ doi: https://dx.doi.org/10.2210/pdb3ZWF/pdb
  15. ↑ Dominski Z. Nucleases of the metallo-beta-lactamase family and their role in DNA and RNA metabolism. Crit Rev Biochem Mol Biol. 2007 Mar-Apr;42(2):67-93. doi:, 10.1080/10409230701279118. PMID:17453916 doi:http://dx.doi.org/10.1080/10409230701279118
  16. ↑ https://doi.org/10.1101/575373
  17. ↑ doi: https://dx.doi.org/https
  18. ↑ https://doi.org/10.1101/575373
  19. ↑ https://doi.org/10.1101/575373

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