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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This is a default text for your page '''Sandbox GGC5'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.
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You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.
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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. In non-muscle cells, titin plays a role in chromosome condensation and chromosome segregation during mitosis.
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On the cellular level, titin is typically located within the nucleus of the cell; however, it can also be located within the cytoplasm.
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=='''Background Information'''==
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== Disease ==
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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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'''Myopathy, myofibrillar, 9, with early respiratory failure:'''
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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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This disease is characterized by adult onset of weakness in proximal, distal, axial 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.
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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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'''Cardiomyopathy, familial hypertrophic 9:'''
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[[Image:Penicillin inhibition.svg]]
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Penicillin inhibition
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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. The symptoms of this disease include: difficult/labored breathing, fainting, collapse, palpitations and chest pains. These symptoms are readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. This disease is characterized by a variant in position 740.
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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, dilated 1G:'''
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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 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.
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=='''Structural highlights'''==
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'''Tardive tibial muscular dystrophy:'''
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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 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.
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''Unique Ligands''
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'''Muscular dystrophy, limb-girdle, autosomal recessive 10:'''
 
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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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<scene name='78/781193/Po4/1'>PO4 Ligand</scene>
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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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== Relevance ==
 
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== Structural highlights ==
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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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•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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- 2007 hydrophobic amino acid residues <ref>DOI 10.2210/pdb3ZWF/pdb</ref>.
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<scene name='78/781193/Hydrophobic_amino_acids/1'>hydrophobic amino acid properties </scene>
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•This secondary structure of titin highlights the <scene name='78/781193/Hydrophobic_structure_tc/1'>Polar.</scene> sections 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.
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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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•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.
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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 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.
 
</StructureSection>
</StructureSection>
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== References ==
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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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== '''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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== '''References''' ==
<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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