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PDBsum entry 5lls
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PDB id:
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Hydrolase
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Title:
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Porcine dipeptidyl peptidase iv in complex with 8-(3-aminopiperidin-1- yl)-7-[(2-bromophenyl)methyl]-1,3-dimethyl-2,3,6,7-tetrahydro-1h- purine-2,6-dione
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Structure:
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Dipeptidyl peptidase 4. Chain: a, b, c, d. Synonym: dipeptidyl peptidase iv,dpp iv,t-cell activation antigen cd26. Ec: 3.4.14.5
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Source:
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Sus scrofa. Pig. Organism_taxid: 9823
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Resolution:
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2.41Å
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R-factor:
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0.192
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R-free:
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0.228
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Authors:
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H.Nar,M.Blaesse
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Key ref:
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G.Schnapp
et al.
(2016).
Comparative Analysis of Binding Kinetics and Thermodynamics of Dipeptidyl Peptidase-4 Inhibitors and Their Relationship to Structure.
J Med Chem,
59,
7466-7477.
PubMed id:
DOI:
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Date:
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28-Jul-16
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Release date:
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14-Sep-16
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PROCHECK
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Headers
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References
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P22411
(DPP4_PIG) -
Dipeptidyl peptidase 4 from Sus scrofa
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Seq:
Struc:
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766 a.a.
727 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.3.4.14.5
- dipeptidyl-peptidase Iv.
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Reaction:
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Release of an N-terminal dipeptide, Xaa-Xbb-|-Xcc, from a polypeptide, preferentially when Xbb is Pro, provided Xcc is neither Pro nor hydroxyproline.
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DOI no:
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J Med Chem
59:7466-7477
(2016)
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PubMed id:
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Comparative Analysis of Binding Kinetics and Thermodynamics of Dipeptidyl Peptidase-4 Inhibitors and Their Relationship to Structure.
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G.Schnapp,
T.Klein,
Y.Hoevels,
R.A.Bakker,
H.Nar.
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ABSTRACT
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The binding kinetics and thermodynamics of dipeptidyl peptidase (DPP)-4
inhibitors (gliptins) were investigated using surface plasmon resonance and
isothermal titration calorimetry. Binding of gliptins to DPP-4 is a rapid
electrostatically driven process. Off-rates were generally slow partly because
of reversible covalent bond formation by some gliptins, and partly because of
strong and extensive interactions. Binding of all gliptins is enthalpy-dominated
due to strong ionic interactions and strong solvent-shielded hydrogen bonds.
Using a congeneric series of molecules which represented the intermediates in
the lead optimization program of linagliptin, the onset of slow binding kinetics
and development of the thermodynamic repertoire were analyzed in the context of
incremental changes of the chemical structures. All compounds rapidly
associated, and therefore the optimization of affinity and residence time is
highly correlated. The major contributor to the increasing free energy of
binding was a strong increase of binding enthalpy, whereas entropic
contributions remained low and constant despite significant addition of
lipophilicity.
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