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The crystal structure indicates that tetramerization of DP IV is a key mechanism to regulate its interaction with other components. Each subunit comprises two structural domains, the N-terminal eight-bladed \u03b2-propeller with open Velcro topology and the C-terminal \u03b1\/\u03b2-hydrolase domain. Analogy with the structurally related POP and tricorn protease suggests that substrates access the buried active site through the \u03b2-propeller tunnel while products leave the active site through a separate side exit. A dipeptide mimicking inhibitor complexed to the active site discloses key determinants for substrate recognition, including a Glu\u2013Glu motif that distinguishes DP IV as an aminopeptidase and an oxyanion trap that binds and activates the P<jats:sub>2<\/jats:sub>-carbonyl oxygen necessary for efficient postproline cleavage. We discuss active and nonactive site-directed inhibition strategies of this pharmaceutical target protein.<\/jats:p>","DOI":"10.1073\/pnas.0230620100","type":"journal-article","created":{"date-parts":[[2003,4,29]],"date-time":"2003-04-29T16:23:56Z","timestamp":1051633436000},"page":"5063-5068","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":267,"title":["The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism"],"prefix":"10.1073","volume":"100","author":[{"given":"Michael","family":"Engel","sequence":"first","affiliation":[{"name":"Max-Planck-Institut f\u00fcr Biochemie, Abt. 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Strukturforschung, D-82152 Martinsried, Germany; Probiodrug AG, Weinbergweg 22\/Biozentrum, D-06120 Halle\/Saale, Germany; and Proteros Biostructures GmbH, Am Klopferspitz 19, D-82152 Martinsried, Germany"}]},{"given":"Reiner","family":"Kiefersauer","sequence":"additional","affiliation":[{"name":"Max-Planck-Institut f\u00fcr Biochemie, Abt. Strukturforschung, D-82152 Martinsried, Germany; Probiodrug AG, Weinbergweg 22\/Biozentrum, D-06120 Halle\/Saale, Germany; and Proteros Biostructures GmbH, Am Klopferspitz 19, D-82152 Martinsried, Germany"}]},{"given":"Robert","family":"Huber","sequence":"additional","affiliation":[{"name":"Max-Planck-Institut f\u00fcr Biochemie, Abt. 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