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Substrate complexes of human dipeptidyl peptidase III reveal the mechanism of enzyme inhibition.

Kumar P, Reithofer V, Reisinger M, Wallner S, Pavkov-Keller T, Macheroux P, Gruber K
Sci Rep 6 23787 (2016)
Related entries: 5e2q, 5e3a, 5e3c, 5egy, 5ehh

Cited: 23 times
EuropePMC logo PMID: 27025154

Abstract

Human dipeptidyl-peptidase III (hDPP III) is a zinc-dependent hydrolase cleaving dipeptides off the N-termini of various bioactive peptides. Thus, the enzyme is likely involved in a number of physiological processes such as nociception and is also implicated in several forms of cancer. We present high-resolution crystal structures of hDPP III in complex with opioid peptides (Met-and Leu-enkephalin, endomorphin-2) as well as with angiotensin-II and the peptide inhibitor IVYPW. These structures confirm the previously reported large conformational change of the enzyme upon ligand binding and show that the structure of the closed conformation is independent of the nature of the bound peptide. The overall peptide-binding mode is also conserved ensuring the correct positioning of the scissile peptide bond with respect to the catalytic zinc ion. The structure of the angiotensin-II complex shows, how longer peptides are accommodated in the binding cleft of hDPP III. Differences in the binding modes allow a distinction between real substrates and inhibitory peptides or "slow" substrates. The latter displace a zinc bound water molecule necessitating the energetically much less favoured anhydride mechanism as opposed to the favoured promoted-water mechanism. The structural data also form the necessary framework for the design of specific hDPP III inhibitors.

Articles - 5e33 mentioned but not cited (8)

  1. Substrate complexes of human dipeptidyl peptidase III reveal the mechanism of enzyme inhibition. Kumar P, Reithofer V, Reisinger M, Wallner S, Pavkov-Keller T, Macheroux P, Gruber K. Sci Rep 6 23787 (2016)
  2. The first dipeptidyl peptidase III from a thermophile: Structural basis for thermal stability and reduced activity. Sabljić I, Tomin M, Matovina M, Sučec I, Tomašić Paić A, Tomić A, Abramić M, Tomić S. PLoS One 13 e0192488 (2018)
  3. Demystifying DPP III Catalyzed Peptide Hydrolysis-Computational Study of the Complete Catalytic Cycle of Human DPP III Catalyzed Tynorphin Hydrolysis. Tomić A, Tomić S. Int J Mol Sci 23 1858 (2022)
  4. Structural and Functional Characterization of a New Bacterial Dipeptidyl Peptidase III Involved in Fruiting Body Formation in Myxobacteria. Chen SB, Zhang H, Chen S, Ye XF, Li ZK, Liu WD, Cui ZL, Huang Y. Int J Mol Sci 24 631 (2022)
  5. Molecular Dynamics Simulations Study of the Interactions between Human Dipeptidyl-Peptidase III and Two Substrates. Zhang S, Lv S, Fu X, Han L, Han W, Li W. Molecules 26 6492 (2021)
  6. Conservation of the conformational dynamics and ligand binding within M49 enzyme family. Kazazić S, Karačić Z, Sabljić I, Agić D, Tomin M, Abramić M, Dadlez M, Tomić A, Tomić S. RSC Adv 8 13310-13322 (2018)
  7. Identification of an Additional Metal-Binding Site in Human Dipeptidyl Peptidase III. Matić A, Šupljika F, Brkić H, Jurasović J, Karačić Z, Tomić S. Int J Mol Sci 24 12747 (2023)
  8. Influence of Mutations of Conserved Arginines on Neuropeptide Binding in the DPP III Active Site. Tomić A, Karačić Z, Tomić S. Molecules 28 1976 (2023)


Reviews citing this publication (2)

  1. Survey of Dipeptidyl Peptidase III Inhibitors: From Small Molecules of Microbial or Synthetic Origin to Aprotinin. Abramić M, Agić D. Molecules 27 3006 (2022)
  2. DPP3: From biomarker to therapeutic target of cardiovascular diseases. Ye P, Duan W, Leng YQ, Wang YK, Tan X, Wang WZ. Front Cardiovasc Med 9 974035 (2022)

Articles citing this publication (13)

  1. Dipeptidyl peptidase 3 modulates the renin-angiotensin system in mice. Jha S, Taschler U, Domenig O, Poglitsch M, Bourgeois B, Pollheimer M, Pusch LM, Malovan G, Frank S, Madl T, Gruber K, Zimmermann R, Macheroux P. J Biol Chem 295 13711-13723 (2020)
  2. Crystal structure of dipeptidyl peptidase III from the human gut symbiont Bacteroides thetaiotaomicron. Sabljić I, Meštrović N, Vukelić B, Macheroux P, Gruber K, Luić M, Abramić M. PLoS One 12 e0187295 (2017)
  3. Concerted nitrogen inversion and hydrogen bonding to Glu451 are responsible for protein-controlled suppression of the reverse reaction in human DPP III. Tomić A, Kovačević B, Tomić S. Phys Chem Chem Phys 18 27245-27256 (2016)
  4. The Development of Translational Biomarkers as a Tool for Improving the Understanding, Diagnosis and Treatment of Chronic Neuropathic Pain. Buckley DA, Jennings EM, Burke NN, Roche M, McInerney V, Wren JD, Finn DP, McHugh PC. Mol Neurobiol 55 2420-2430 (2018)
  5. Coumarin Derivatives Act as Novel Inhibitors of Human Dipeptidyl Peptidase III: Combined In Vitro and In Silico Study. Agić D, Karnaš M, Šubarić D, Lončarić M, Tomić S, Karačić Z, Bešlo D, Rastija V, Molnar M, Popović BM, Lisjak M. Pharmaceuticals (Basel) 14 540 (2021)
  6. Validation of flavonoids as potential dipeptidyl peptidase III inhibitors: Experimental and computational approach. Agić D, Brkić H, Tomić S, Karačić Z, Špoljarević M, Lisjak M, Bešlo D, Abramić M. Chem Biol Drug Des 89 619-627 (2017)
  7. Circulating dipeptidyl peptidase 3 on intensive care unit admission is a predictor of organ dysfunction and mortality. Frigyesi A, Lengquist M, Spångfors M, Annborn M, Cronberg T, Nielsen N, Levin H, Friberg H. J Intensive Care 9 52 (2021)
  8. Dipeptidyl peptidase 3, a novel protease from Leishmania braziliensis. Diaz JR, Ramírez CA, Nocua PA, Guzman F, Requena JM, Puerta CJ. PLoS One 13 e0190618 (2018)
  9. A novel Porphyromonas gingivalis enzyme: An atypical dipeptidyl peptidase III with an ARM repeat domain. Hromić-Jahjefendić A, Jajčanin Jozić N, Kazazić S, Grabar Branilović M, Karačić Z, Schrittwieser JH, Das KMP, Tomin M, Oberer M, Gruber K, Abramić M, Tomić S. PLoS One 12 e0188915 (2017)
  10. Efficient Entropy-Driven Inhibition of Dipeptidyl Peptidase III by Hydroxyethylene Transition-State Peptidomimetics. Ivkovic J, Jha S, Lembacher-Fadum C, Puschnig J, Kumar P, Reithofer V, Gruber K, Macheroux P, Breinbauer R. Chemistry 27 14108-14120 (2021)
  11. Dipeptidyl Peptidase 3 Activity as a Promising Biomarker of Bone Fragility in Postmenopausal Women. Menale C, Tabacco G, Naciu AM, Schiavone ML, Cannata F, Morenghi E, Sobacchi C, Palermo A. Molecules 27 3929 (2022)
  12. Triarylborane Dyes as a Novel Non-Covalent and Non-Inhibitive Fluorimetric Markers for DPP III Enzyme. Ban Ž, Karačić Z, Tomić S, Amini H, Marder TB, Piantanida I. Molecules 26 4816 (2021)
  13. Health Beneficial Bioactivities of Faba Bean Gastrointestinal (In Vitro) Digestate in Comparison to Soybean and Pea. Martineau-Côté D, Achouri A, Wanasundara J, Karboune S, L'Hocine L. Int J Mol Sci 23 9210 (2022)


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