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== <scene name='79/799598/Cartoon_view_of_kgp/3'>Function</scene> ==
== <scene name='79/799598/Cartoon_view_of_kgp/3'>Function</scene> ==
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The protein being studied in this article is KGP <ref>PMID:25266723</ref>. 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. KGP uses cysteine to cleave proteins containing Lys-X. KGP always cuts after lysine residues <ref>PMID:21660656</ref>. The substrate is any peptide that contains a Lysine. Substrate XXLXX and the product would be XXL + XX.
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The protein being studied in this article is KGP <ref>PMID:25266723</ref>. 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. KGP uses cysteine to cleave proteins containing Lys-X. KGP always cuts after lysine residues <ref>PMID:21660656</ref>. The substrate is any peptide that contains a Lysine. Substrate XXLXX and the product would be XXL + XX.
==Disease==
==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.
''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.
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== Structural highlights ==
== Structural highlights ==
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The<scene name='79/799598/Secondary_structure_of_kgp/1'> secondary structure</scene> 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. For KGP, the secondary structure elements are generally connected by tight loops. The structure of KGP is broken up into a catalytic domain and an IGSF. The globular CD contains four cation binding sites (two sodium and two calcium ions) that generally contribute to the integrity of the <scene name='79/799598/Tertiary_structure/1'>tertiary structure</scene>. It is subdivided into a smaller A subdomain that contains the N-terminus which is highlighted in pink. It also contains a larger B subdomain that contains the C-terminus which is shown in orange. The light blue portion of the protein represents the IGSF, which is essential for folding of KGP. The IGSF fold corresponds to typical IGSF like domains, which usually function as cell adhesion molecules. By viewing KGP under the <scene name='79/799598/Space_fill_without_hydrophob/1'>space fill</scene> 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 <scene name='79/799598/Space_fill_view/2'>hydrophibictity</scene> 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. The <scene name='79/799598/Ckc_ligand/1'>Ligand</scene> 'CKC' is a lysine mimic that binds to KGP and is recognized by the cysteine peptidase to cleave Lys-X. KGP contains a <scene name='79/799598/Triad_interacting_with_ckc/1'>catalytic triad</scene> Cys-477, His-444, Asp-388. The catalytic triad interacts with the ligand CKC. Histidine and aspartic acid use acid base chemistry catalysis to form a covalent intermediate with Cysteine 477. The intermediate formed is L-lysinylmethyl (LM) group in the specificity pocket. The <scene name='79/799598/Active_site/1'>active site</scene> is shown with the catalytic triad in red, and other amino acid residues that interact in the specificity pocket. KGP contains a set of alpha helices that are interrupted by a <scene name='79/799598/Interrupted_alpha_helices/1'>segment</scene> of the protein that contains glycine and proline amino acids. These residues, highlighted in red, are alpha helix breakers as glycine is too small and proline contains a ring structure that prevents the alpha helix from forming. These interrupted alpha helices are exceedingly rare in protein structures. CSD domain of the protein contains an internal channel that vertically traverses the molecule over 20 Angstroms from the bottom of the specificity pocket in the active site to the lower outer surface of the subdomain. The channel emerges through a <scene name='79/799598/Internal_channel_amino_acids/1'>crater</scene> surrounded by the amino acids shown in the JSmol. KGP interacts with various <scene name='79/799598/Ion_site_of_ca998/1'>ions</scene> through solvent channels. This JSmol shows various amino acid residues interacting with a calcium ion.
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The<scene name='79/799598/Secondary_structure_of_kgp/1'> secondary structure</scene> 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 certain areas of the protein. For KGP, the secondary structure elements are generally connected by tight loops. The structure of KGP is broken up into a catalytic domain and an IGSF. The globular CD contains four cation binding sites (two sodium and two calcium ions) that generally contribute to the integrity of the <scene name='79/799598/Tertiary_structure/1'>tertiary structure</scene>. It is subdivided into a smaller A subdomain that contains the N-terminus which is highlighted in pink. It also contains a larger B subdomain that contains the C-terminus which is shown in orange. The light blue portion of the protein represents the IGSF, which is essential for folding of KGP. The IGSF fold corresponds to typical IGSF like domains, which usually function as cell adhesion molecules. By viewing KGP under the <scene name='79/799598/Space_fill_without_hydrophob/1'>space fill</scene> 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 <scene name='79/799598/Space_fill_view/2'>hydrophibictity</scene> 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. The <scene name='79/799598/Ckc_ligand/1'>Ligand</scene> 'CKC' is a lysine mimic that binds to KGP and is recognized by the cysteine peptidase to cleave Lys-X. KGP contains a <scene name='79/799598/Triad_interacting_with_ckc/1'>catalytic triad</scene> Cys-477, His-444, Asp-388. The catalytic triad interacts with the ligand CKC. Histidine and aspartic acid use acid base chemistry catalysis to form a covalent intermediate with Cysteine 477. The intermediate formed is L-lysinylmethyl (LM) group in the specificity pocket. The <scene name='79/799598/Active_site/1'>active site</scene> is shown with the catalytic triad in red, and other amino acid residues that interact in the specificity pocket. KGP contains a set of alpha helices that are interrupted by a <scene name='79/799598/Interrupted_alpha_helices/1'>segment</scene> of the protein that contains glycine and proline amino acids. These residues, highlighted in red, are alpha helix breakers as glycine is too small and proline contains a ring structure that prevents the alpha helix from forming. These interrupted alpha helices are exceedingly rare in protein structures. CSD domain of the protein contains an internal channel that vertically traverses the molecule over 20 Angstroms from the bottom of the specificity pocket in the active site to the lower outer surface of the subdomain. The channel emerges through a <scene name='79/799598/Internal_channel_amino_acids/1'>crater</scene> surrounded by the amino acids shown in the JSmol. KGP interacts with various <scene name='79/799598/Ion_site_of_ca998/1'>ions</scene> through solvent channels. This JSmol shows various amino acid residues interacting with a calcium ion.
</StructureSection>
</StructureSection>
== References ==
== References ==
<references/>
<references/>

Revision as of 00:18, 15 November 2018

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 gingivitis in Periodontitis

Structure

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References

  1. de Diego I, Veillard F, Sztukowska M, Guevara T, Potempa B, Pomowski A, Huntington JA, Potempa J, Gomis-Ruth FX. Structure and mechanism of cysteine peptidase Kgp, a major virulence factor of Porphyromonas gingivalis in periodontitis. J Biol Chem. 2014 Sep 29. pii: jbc.M114.602052. PMID:25266723 doi:http://dx.doi.org/10.1074/jbc.M114.602052
  2. Yongqing T, Potempa J, Pike RN, Wijeyewickrema LC. The lysine-specific gingipain of Porphyromonas gingivalis : importance to pathogenicity and potential strategies for inhibition. Adv Exp Med Biol. 2011;712:15-29. doi: 10.1007/978-1-4419-8414-2_2. PMID:21660656 doi:http://dx.doi.org/10.1007/978-1-4419-8414-2_2
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