title: Synthetic derivatives of the SUMO consensus sequence provide a basis for improved substrate recognition.
abstract: Protein sumoylation is a dynamic posttranslational modification that regulates a diverse subset of the proteome. The mechanism by which sumoylation enzymes recognize their cognate substrates is unclear, and the consequences of sumoylation remain difficult to predict. While small molecule probes of the sumoylation process could be valuable for understanding SUMO biology, few small molecules that modulate this process exist. Here, we report the synthesis and evaluation of over 600 oxime-containing peptide sumoylation substrates. Our work demonstrates that higher modification efficiency can be achieved with non-natural side chains that deviate substantially from the consensus site requirement of a hydrophobic substituent. Furthermore, docking studies suggest that these improved substrates mimic binding interactions that are used by other endogenous protein sequences through tertiary interactions. The development of these high efficiency substrates provides key mechanistic insights toward specific recognition of low molecular weight species in the sumoylation pathway.
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute, 376 Boyles St., Frederick, MD 21702, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Leyva
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute, 376 Boyles St., Frederick, MD 21702, USA.
authors.forename: Yeong Sang
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Basic Science Program, Chemical Biology Laboratory, Leidos Biomedical Research, Inc., National Cancer Institute, 376 Boyles St., Frederick, MD 21702, USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Peach
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute, 376 Boyles St., Frederick, MD 21702, USA. Electronic address: schneeklothjs@mail.nih.gov.
authors.forename: John S
authors.initials: JS
authors.lastname: Schneekloth
mesh_terms: D016384:Consensus Sequence; D025841:Small Ubiquitin-Related Modifier Proteins / Q000737:chemistry*; D013379:Substrate Specificity; D058207:Sumoylation
chemical_list: D025841:Small Ubiquitin-Related Modifier Proteins
keywords: Combinatorial chemistry; Conjugation; Enzymes; Peptide mimics; SUMO