2g5t

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2g5t, resolution 2.30Å ()
Ligands:
Gene: DPP4, ADCP2, CD26 (Homo sapiens)
Activity: Dipeptidyl-peptidase IV, with EC number 3.4.14.5
Related: 2g5p
Resources: FirstGlance, OCA, PDBsum, RCSB
Coordinates: save as pdb, mmCIF, xml



Contents

Crystal structure of human dipeptidyl peptidase IV (DPPIV) complexed with cyanopyrrolidine (C5-pro-pro) inhibitor 21ag

Publication Abstract from PubMed

A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K(i)'s, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.

Discovery, structure-activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors., Pei Z, Li X, Longenecker K, von Geldern TW, Wiedeman PE, Lubben TH, Zinker BA, Stewart K, Ballaron SJ, Stashko MA, Mika AK, Beno DW, Long M, Wells H, Kempf-Grote AJ, Madar DJ, McDermott TS, Bhagavatula L, Fickes MG, Pireh D, Solomon LR, Lake MR, Edalji R, Fry EH, Sham HL, Trevillyan JM, J Med Chem. 2006 Jun 15;49(12):3520-35. PMID:16759095

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

About this Structure

2g5t is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

See Also

Reference

  • Pei Z, Li X, Longenecker K, von Geldern TW, Wiedeman PE, Lubben TH, Zinker BA, Stewart K, Ballaron SJ, Stashko MA, Mika AK, Beno DW, Long M, Wells H, Kempf-Grote AJ, Madar DJ, McDermott TS, Bhagavatula L, Fickes MG, Pireh D, Solomon LR, Lake MR, Edalji R, Fry EH, Sham HL, Trevillyan JM. Discovery, structure-activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors. J Med Chem. 2006 Jun 15;49(12):3520-35. PMID:16759095 doi:10.1021/jm051283e

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