6Y0F

Structure of human FAPalpha in complex with linagliptin

Summary for 6Y0F

• Entry DOI: 10.2210/pdb6y0f/pdb
• Descriptor: Prolyl endopeptidase FAP, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: fap inhibitor complex dpp4 linagliptin, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 341544.60

Authors

Nar, H.,Schnapp, G.,Schreiner, P. (deposition date: 2020-02-07, release date: 2021-02-17, Last modification date: 2026-03-25)

Primary citation

Schnapp, G.,Hoevels, Y.,Bakker, R.A.,Schreiner, P.,Klein, T.,Nar, H.
A Single Second Shell Amino Acid Determines Affinity and Kinetics of Linagliptin Binding to Type 4 Dipeptidyl Peptidase and Fibroblast Activation Protein.
Chemmedchem, 16:630-639, 2021

PubMed Abstract: Drugs targeting type 4 dipeptidyl peptidase (DPP-4) are beneficial for glycemic control, whereas fibroblast activation protein alpha (FAP-α) is a potential target for cancer therapies. Unlike other gliptins, linagliptin displays FAP inhibition. We compared biophysical and structural characteristics of linagliptin binding to DPP-4 and FAP to better understand what differentiates linagliptin from other gliptins. Linagliptin exhibited high binding affinity (K ) and a slow off-rate (k ) when dissociating from DPP-4 (K 6.6 pM; k 5.1×10  s ), and weaker inhibitory potency to FAP (K 301 nM; k >1 s ). Co-structures of linagliptin with DPP-4 or FAP were similar except for one second shell amino acid difference: Asp663 (DPP-4) and Ala657 (FAP). pH dependence of enzymatic activities and binding of linagliptin for DPP-4 and FAP are dependent on this single amino acid difference. While linagliptin may not display any anticancer activity at therapeutic doses, our findings may guide future studies for the development of optimized inhibitors.

PubMed: 33030297
DOI: 10.1002/cmdc.202000591

Experimental method

X-RAY DIFFRACTION (2.924 Å)