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From Proteopedia
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<StructureSection load='' size='340' side='right' caption='Click the links to load figures an animate' scene=''> | <StructureSection load='' size='340' side='right' caption='Click the links to load figures an animate' scene=''> | ||
== Structure == | == Structure == | ||
| - | Dipeptidyl peptidase – IV (DPP-IV) is a serine protease, also called adenosine deaminase (ADA) binding protein or CD26. The enzyme is a chain of 766 amino acids and exists in the body as a homodimer. Each monomer of DPP-IV consists of two domains: an 8-bladed β-propeller domain (res. 61-495, shown in green), and a α/β hydrolase domain (res. 39-55 and 497-766, shown in red). | + | Dipeptidyl peptidase – IV (DPP-IV) is a serine protease, also called adenosine deaminase (ADA) binding protein or CD26. The enzyme is a chain of 766 amino acids and exists in the body as a homodimer. Each monomer of DPP-IV consists of two domains: an 8-bladed β-propeller domain (res. 61-495, shown in green), and a α/β hydrolase domain (res. 39-55 and 497-766, shown in red). <sup>[1]</sup> |
<jmol><jmollink><text>View Figure 1: DPP-IV Dimer</text><script>exit;figure=1;SCRIPT "http://proteopedia.org/wiki/images/7/74/Dimer.png"</script></jmollink></jmol> | <jmol><jmollink><text>View Figure 1: DPP-IV Dimer</text><script>exit;figure=1;SCRIPT "http://proteopedia.org/wiki/images/7/74/Dimer.png"</script></jmollink></jmol> | ||
<jmol><jmollink><text>View Figure 1: Animate </text><script>exit;figure=1;SCRIPT "http://proteopedia.org/wiki/images/8/83/Dimerscriptupdated.spt"</script></jmollink></jmol> | <jmol><jmollink><text>View Figure 1: Animate </text><script>exit;figure=1;SCRIPT "http://proteopedia.org/wiki/images/8/83/Dimerscriptupdated.spt"</script></jmollink></jmol> | ||
| - | The active site of DPP-IV is located in a large cavity located between the two domains. This cavity has two openings to the active site: one large hole at the interface between the domains, and a smaller hole formed by the β-propeller domain. | + | The active site of DPP-IV is located in a large cavity located between the two domains. This cavity has two openings to the active site: one large hole at the interface between the domains, and a smaller hole formed by the β-propeller domain. <sup>[2]</sup> |
<jmol><jmollink><text>View Figure 2: Binding Cavity of DPP-IV </text><script>exit;figure=1;SCRIPT "/wiki/images/6/64/Cachedisosurface.png"</script></jmollink></jmol> | <jmol><jmollink><text>View Figure 2: Binding Cavity of DPP-IV </text><script>exit;figure=1;SCRIPT "/wiki/images/6/64/Cachedisosurface.png"</script></jmollink></jmol> | ||
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== Function == | == Function == | ||
| - | DPP-IV is involved in the inactivation of incretins, degradation of non-incretin peptides, and other non-enzymatic functions. Because of this, DPP-IV acts on a wide range of substrates: chemokines (RANTES, MDC, IP-10, etc.), neuropeptides (NPY, Peptide YY, etc.), and regulatory peptides (GLP-1, GLP-2, GIP, etc.). DPP-IV acts on a substrate by hydrolyzing the amide bond at the penultimate residue from its N-terminus, which is either a proline or alanine. For example, the substrate GLP-1 (an incretin important to diabetes research) contains an Ala-His sequence which is cleaved off by DPP-IV. | + | DPP-IV is involved in the inactivation of incretins, degradation of non-incretin peptides, and other non-enzymatic functions. Because of this, DPP-IV acts on a wide range of substrates: chemokines (RANTES, MDC, IP-10, etc.), neuropeptides (NPY, Peptide YY, etc.), and regulatory peptides (GLP-1, GLP-2, GIP, etc.). <sup>[3]</sup> DPP-IV acts on a substrate by hydrolyzing the amide bond at the penultimate residue from its N-terminus, which is either a proline or alanine. <sup>[4]</sup> For example, the substrate GLP-1 (an incretin important to diabetes research) contains an Ala-His sequence which is cleaved off by DPP-IV. <sup>[5]</sup> |
Research has shown that large substrates like GLP-1 enter DPP-IV through the large cavity formed between its α/β and β domains. After it is cleaved, the large remaining portion of the substrate exits through the same cavity. It is believed that the dipeptide may exit the cavity through the smaller hole formed by the beta-propeller region. Antidiabetic drugs called gliptins target and inhibit the DPP-IV enzyme. | Research has shown that large substrates like GLP-1 enter DPP-IV through the large cavity formed between its α/β and β domains. After it is cleaved, the large remaining portion of the substrate exits through the same cavity. It is believed that the dipeptide may exit the cavity through the smaller hole formed by the beta-propeller region. Antidiabetic drugs called gliptins target and inhibit the DPP-IV enzyme. | ||
| - | Incretins such GLP-1 typically decrease glucose in the blood. When hydrolyzed by DPP-IV, they can no longer defend against high blood glucose. By inhibiting DPP-IV, gliptins increase the number of functional incretins and effectively lower blood glucose. | + | Incretins such GLP-1 typically decrease glucose in the blood. When hydrolyzed by DPP-IV, they can no longer defend against high blood glucose. By inhibiting DPP-IV, gliptins increase the number of functional incretins and effectively lower blood glucose. <sup>[6]</sup> |
<jmol><jmollink><text>View Figure 3: GLP-1 Enters and Exits Binding Pocket and is Cleaved</text><script>exit;figure=1;SCRIPT "/wiki/images/0/02/Ani5.png"</script></jmollink></jmol> | <jmol><jmollink><text>View Figure 3: GLP-1 Enters and Exits Binding Pocket and is Cleaved</text><script>exit;figure=1;SCRIPT "/wiki/images/0/02/Ani5.png"</script></jmollink></jmol> | ||
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</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
| - | + | [1]. Hiramatsu, H., Kyono, K., Higashiyama, Y., Fukushima, C., Shima, H., Sugiyama, S., Inaka, K., Yamamoto, A., and Shimizu, R. (2003) The structure and function of human dipeptidyl peptidase IV, possessing a unique eight-bladed -propeller fold. Biochemical and Biophysical Research Communications 302, 849–854. doi:10.1016/s0006-291x(03)00258-4 | |
| + | [2]. Klemann C, Wagner L, Stephan M, von Hörsten S. Cut to the chase: a review of CD26/dipeptidyl peptidase‐4’s (DPP4) entanglement in the immune system. Clinical and Experimental Immunology. 2016;185(1):1-21. doi:10.1111/cei.12781. | ||
| + | [3]. Zhong, J., Rao, X., and Rajagopalan, S. (2013) An emerging role of dipeptidyl peptidase 4 (DPP4) beyond glucose control: potential implications in cardiovascular disease. Atherosclerosis, 226, 305-314. doi: 10.1016/j.atherosclerosis.2012.09.012 | ||
| + | [4]. Aertgeerts, K., Ye, S., Tennant, M. G., Kraus, M. L., Rogers, J., Sang, B.-C., Skene, R. J., Webb, D. R. and Prasad, G. S. (2004), Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation. Protein Science, 13: 412–421. doi:10.1110/ps.03460604 | ||
| + | [5]. Chang, X., et al. “Structure and Folding of Glucagon-like Peptide-1-(7-36)-Amide in Trifluoroethanol Studied by NMR.” RCSB PDB, www.rcsb.org/structure/1D0R. | ||
| + | [6]. Dipeptidyl Peptidase-4 (DPP-4). (n.d.). Retrieved January 28, 2018, from https://pdb101.rcsb.org/global-health/diabetes-mellitus/drugs/dpp4-inhibitor/dpp4 | ||
Revision as of 03:03, 30 January 2018
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References
[1]. Hiramatsu, H., Kyono, K., Higashiyama, Y., Fukushima, C., Shima, H., Sugiyama, S., Inaka, K., Yamamoto, A., and Shimizu, R. (2003) The structure and function of human dipeptidyl peptidase IV, possessing a unique eight-bladed -propeller fold. Biochemical and Biophysical Research Communications 302, 849–854. doi:10.1016/s0006-291x(03)00258-4 [2]. Klemann C, Wagner L, Stephan M, von Hörsten S. Cut to the chase: a review of CD26/dipeptidyl peptidase‐4’s (DPP4) entanglement in the immune system. Clinical and Experimental Immunology. 2016;185(1):1-21. doi:10.1111/cei.12781. [3]. Zhong, J., Rao, X., and Rajagopalan, S. (2013) An emerging role of dipeptidyl peptidase 4 (DPP4) beyond glucose control: potential implications in cardiovascular disease. Atherosclerosis, 226, 305-314. doi: 10.1016/j.atherosclerosis.2012.09.012 [4]. Aertgeerts, K., Ye, S., Tennant, M. G., Kraus, M. L., Rogers, J., Sang, B.-C., Skene, R. J., Webb, D. R. and Prasad, G. S. (2004), Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation. Protein Science, 13: 412–421. doi:10.1110/ps.03460604 [5]. Chang, X., et al. “Structure and Folding of Glucagon-like Peptide-1-(7-36)-Amide in Trifluoroethanol Studied by NMR.” RCSB PDB, www.rcsb.org/structure/1D0R. [6]. Dipeptidyl Peptidase-4 (DPP-4). (n.d.). Retrieved January 28, 2018, from https://pdb101.rcsb.org/global-health/diabetes-mellitus/drugs/dpp4-inhibitor/dpp4
