9y3m
Crystal Structure of Human Ornithine Aminotransferase Pre-inactivated by CPP115 (Covalent Inactivation)
Structural highlights
DiseaseOAT_HUMAN Defects in OAT are the cause of hyperornithinemia with gyrate atrophy of choroid and retina (HOGA) [MIM:258870. HOGA is a slowly progressive blinding autosomal recessive disorder.[1] [2] [3] [4] [5] [6] FunctionPublication Abstract from PubMedCurrently, mechanism-based inactivators (MBIs) are the only available therapeutic option to target gamma-aminobutyric acid aminotransferase (GABA-AT). However, off-target activity against homologous enzymes is a well-recognized challenge for the clinical use of MBIs. For example, CPP-115, an MBI of GABA-AT that completed a Phase I clinical trial, also inactivates ornithine aminotransferase (OAT). Here, we present a comprehensive investigation of an OAT-specific inactivation mechanism for CPP-115 by integrating biochemical experiments, X-ray crystallography, and computational simulations. Unlike in GABA-AT, where CPP-115 forms a noncovalent tight-binding adduct only, a covalent adduct was additionally observed with human OAT (hOAT). Notably, the crystal structures of CPP-115-treated hOAT at different mechanistic stages indicate that the conformational transition of a key intermediate is a prerequisite for the covalent addition pathway. Based on this finding, to selectively reduce the off-target activity, a proof-of-concept molecule that regulates the intermediate conformational flexibility was designed and synthesized. The resulting inactivator achieved greatly enhanced GABA-AT selectivity over OAT and demonstrated therapeutic efficacy in an inflammatory pain animal model. Our strategy in this study, targeting dynamics of a reactive intermediate based on a precise mechanistic understanding, serves as a general design principle for fine-tuning the selectivity of MBIs, particularly for other aminotransferases. Targeting Conformational Flexibility of a Reactive Intermediate to Enhance Selectivity of a GABA Aminotransferase Inactivator.,Kang KM, Vargas AL, Ferreira LA, Des Soye BJ, Corrigan M, Zhang CK, Wang F, Duan D, Kelleher NL, Hohmann AG, Liu D, Silverman RB J Am Chem Soc. 2026 Mar 4;148(8):8736-8748. doi: 10.1021/jacs.5c21138. Epub 2026 , Feb 19. PMID:41711325[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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