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The protein being studied in this article is KGP. This cysteine peptidase is a major virulence factor for the periodontopathogen Porphyromonas gingivalis. KGP works by cleaving many constituents of human connective tissue which leads to decreased bacterial activity and chronic inflammation in the gums. It contains a catalytic triad of cysteine histidine and aspartic acid. The histidine and aspartic acid residues in the catalytic triad use acid base chemistry catalysis to form a covalent intermediate with the cysteine. The intermediate formed is L-lysinylmethyl which is found in the specificity pocket.

Disease

Porphyromonas gingivalis is a Gram-Negative oral anaerobe that leads to periodontitis. It invades periodontal tissues, and evades the host defense mechanisms by a series of virulence factors, such as KGP, that deregulate innate immune and inflammatory responses. This bacteria and its products can enter circulation and contribute to the development of diabetes, cardiovascular disease, and rheumatoid arthritis.

Relevance

Bacteria are typically beneficial to maintaining a healthy mouth, however, if they are a susceptible host they can become pathogenic. Once they become pathogenic they can invade tissues and lead to infection and disease. Resistant strains are currently responsible for half of all infections, and resistant pathogens infect over 2 million people annually in the United States. The only way to keep up with these resistant pathogens is by developing new antimicrobials, but the pharmaceutical industry is failing to keep up. By studying KGP, scientists hope to find a suitable inhibitor to eliminate KGP activity, and thus prevent periodontal disease in humans.

Structural highlights

The of KGP is made up of about equal amounts of alpha helices and antiparallel beta sheets. The secondary structure is important to understand because it provides detail about how the protein is folded due to interactions between amino acids. For example, alpha helices shown in pink contain hydrophilic amino acids facing the solvent (outside) and hydrophobic amino acids facing inside, but the center of the helices is too small for even a hydrogen atom to fit through. Alpha helices and beta sheets cannot contain proline or glycine in their structure, so by simply knowing what the secondary structures are you already have insight into what types of amino acids are found in the protein. By viewing KGP under the view you can see that the protein is very tightly packed and there is little to no room for other molecules to reach the center. The view of KGP shows the protein contains both hydrophilic, shown in pink, and hydrophobic, shown in grey, amino acid residues. The red molecules represent the solvent.