2G5P
Crystal structure of human dipeptidyl peptidase IV (DPPIV) complexed with cyanopyrrolidine (C5-pro-pro) inhibitor 21ac
Summary for 2G5P
| Entry DOI | 10.2210/pdb2g5p/pdb |
| Related | 2G5T |
| Descriptor | Dipeptidyl peptidase 4, 4-{[(2R,5S)-5-{[(2S)-2-(AMINOMETHYL)PYRROLIDIN-1-YL]CARBONYL}PYRROLIDIN-2-YL]METHOXY}-3-TERT-BUTYLBENZOIC ACID (3 entities in total) |
| Functional Keywords | serine peptidase, beta-propeller, hydrolase |
| Biological source | Homo sapiens (human) |
| Cellular location | Dipeptidyl peptidase 4 soluble form: Secreted . Cell membrane ; Single- pass type II membrane protein: P27487 |
| Total number of polymer chains | 2 |
| Total formula weight | 168908.19 |
| Authors | Longenecker, K.L.,Fry, E.H.,Lake, M.R.,Solomon, L.R.,Pei, Z.,Li, X. (deposition date: 2006-02-23, release date: 2006-07-04, Last modification date: 2024-10-16) |
| Primary citation | Pei, Z.,Li, X.,Longenecker, K.,Von Geldern, T.W.,Wiedeman, P.E.,Lubben, T.H.,Zinker, B.A.,Stewart, K.,Ballaron, S.J.,Stashko, M.A.,Mika, A.K.,Beno, D.W.,Long, M.,Wells, H.,Kempf-Grote, A.J.,Madar, D.J.,McDermott, T.S.,Bhagavatula, L.,Fickes, M.G.,Pireh, D.,Solomon, L.R.,Lake, M.R.,Edalji, R.,Fry, E.H.,Sham, H.L.,Trevillyan, J.M. Discovery, structure-activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors. J.Med.Chem., 49:3520-3535, 2006 Cited by PubMed Abstract: 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. PubMed: 16759095DOI: 10.1021/jm051283e PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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