Sandbox Reserved 1456

This Sandbox is Reserved from October 22, 2018 through April 30, 2019 for use in the course Biochemistry taught by Bonnie Hall at the Grand View University, Des Moines, IA USA. This reservation includes Sandbox Reserved 1456 through Sandbox Reserved 1470.

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Structure and Mechanism of Cysteine Peptidase Gingipain K (Kgp), a Major Virulence Factor of Porphyromonas gingivalis in PeriodontitisStructure and Mechanism of Cysteine Peptidase Gingipain K (Kgp), a Major Virulence Factor of Porphyromonas gingivalis in Periodontitis

The protein, Kgp, is being studied in the bacteria Porphyromonas gingivalis. Kgp is a virulence factor of P. gingivalis that cleaves many constituents of connective tissue, leading to decreased bactericidal activity and chronic inflammation of the gums. Virulence is due to nutrient acquisition, cleavage of host cell surface receptors, signaling via protease activated receptors, and inactivation of cytokines and of the complement system. Disease Porphyromonas gingivalis is a Gram-negative oral anaerobe that causes periodontitis. When invaded with Kgp, P. gingivalis degrades the immune and inflammatory response, granting the now-pathogenic bacteria access to the circulatory system. Entry into the circulatory system allows them to cause infection and increase severity of systemic diseases, such as cardiovascular diseases and rheumatoid arthritis. . Relevance Bacteria usually benefit human health, but if they are a susceptible host, they can become pathogenic and cause infection and disease. This is happening at a faster rate as the pathogens become more resistant to antibiotics as time passes and the pharmaceutical industry neglects to create new antimicrobials that could combat the growing virulence of these resistant pathogens. By studying Kgp, scientists hope to find a suitable inhibitor for this protein. Structural highlights The main present in Kgp are alpha helices and antiparallel beta sheets. Alpha helices and beta sheets impact how the protein will fold by allowing for specific amino acid interactions. Alpha helices are tightly wound with a center channel too small for even a hydrogen atom to pass through. Alpha helices and beta sheets cannot have a glycine or proline residue as part of the chain and are only found in beta-turns. By knowing this, you know that glycine and proline would not be found in the primary amino acid sequence where the alpha helices and beta sheets would be found. This shows that the atoms that make up Kgp do not leave much room for other molecules to pass through. The of the surface of Kgp shows a fairly even distribution of hydrophobic (gray) and hydrophilic (purple) atoms. The red atoms are the solvent, and they are interacting with the hydrophilic atoms present on the surface of Kgp. The of this molecule is (3S)-3,7-diaminoheptan-2-one, referred to as CKC. CKC has the same structure as lysine, having two protonated amine groups and a carboxylic acid group all capable of hydrogen bonding. The side chain of CKC contains four carbon groups which allows for a hydrophobic interaction. This molecule hydrogen bonds with the three amino acids of the catalytic triad to stabilize the structure of Kgp. The structure of the complex is maintained by hydrogen bond formation and a hydrophobic interaction with Trp513, thus decreasing entropy of the system and producing a favorable complex. The of Kgp is made up of Cys477-His444-Asp388. The ligand, CKC, is shown in red and the three amino acids of the catalytic triad are colored by elements (CPK). His444 and Asp388 use acid base catalysis with a covalent intermediate formed with Cys477 to cleave the peptide bond. The histidine imidazolium group transfers a proton to the leaving alpha-amine group of the cleavage product, leaving part of the substrate bound covalently as a thioester to the catalytic Cys477. The mechanism of action of Kgp is largely determined by its active site.

spinqualitylabelsall models Structure of Kgp Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image