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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. P. gingivalis degrades the immune and inflammatory response, giving them access to the circulatory system, allowing them to start and increase severity of systemic diseases, such as cardiovascular diseases and rheumatoid arthritis. ^[1].

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 model shows that the atoms that make up Kgp do not leave much room for other molecules to pass through. The surface of the protein is 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

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.