Biomedical Engineering Reference
In-Depth Information
A
B
Figure 5.2
Crystal structure of DPP-4 (PDB code 1X70). (A) Surface representation
of the DPP-4 dimer. The a/b-hydrolase and b-propeller domains are
shown in red and blue, respectively. The DPP-4 inhibitor, sitagliptin
(shown in green stick), denotes the location of the active site. The openings
to the active site of each monomer face 1801 away from each other on
opposite sides. (B) Close-up view of the sitagliptin-bound active site of
DPP-4. The regions of the active site are represented as follows: the cat-
alytic triad Ser630, Asp708 and His740 as magenta, grey, and blue spheres,
respectively; the P2-loop (variable region) in cyan; the R-loop (variable
region) in dark green; and the glutamate-rich helix that contains Glu205-
Glu206 (conserved) in red. Asp663 (yellow sphere) in DPP-4 (equivalent to
Ala657 in FAP) gives rise to the acidic region that leads to greater spe-
cificity of DPP-4 for dipeptide substrates. Sitagliptin is shown in stick
representation, with carbon in green, nitrogen in blue, oxygen in red, and
fluorine in grey. Polar interactions between sitagliptin and the surrounding
DPP-4 structural motifs are denoted by black dotted lines. Rational drug
design for the DPP-4 family of proteins focuses on the variable regions
presented by the P2-loop (cyan) and the R-loop (dark green), and on the
acidic pocket presented by Asp663 (yellow sphere). Some residues that
would otherwise obscure the active site have been omitted to reveal the
hollow cavity found in this protein family. Image generated using
PYMOL (DeLano WL: http://www.pymol.org).
catalytic triad from the a/b-hydrolase domain (Ser630, Asp708, and His740),
and Glu205 and Glu206 from the b-propeller domain, which are essential for
enzyme activity.
52,53
The variability presented by the b-propeller domain and amino acid differ-
ences within the active sites of these proteins makes it possible to design and
generate inhibitors selective for each member of the DPP-4 protein family
(Figure 5.2B). Structurally, access to the internal active site is separate from the
extra-enzymatic ligand-binding sites on the protein surface. Thus, the use of
active site inhibitors is very unlikely to affect extra-enzymatic function.
5.2.4 Substrates of DPP-4
The ubiquitous expression of DPP-4 along with its unique post-proline pep-
tidase activity indicates the importance of this enzyme and its vital activity in
