title: Rational steering of insulin binding specificity by intra-chain chemical crosslinking.
abstract: Insulin is a key hormone of human metabolism with major therapeutic importance for both types of diabetes. New insulin analogues with more physiological profiles and better glycemic control are needed, especially analogues that preferentially bind to the metabolic B-isoform of insulin receptor (IR-B). Here, we aimed to stabilize and modulate the receptor-compatible conformation of insulin by covalent intra-chain crosslinking within its B22-B30 segment, using the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of azides and alkynes. This approach resulted in 14 new, systematically crosslinked insulin analogues whose structures and functions were extensively characterized and correlated. One of the analogues, containing a B26-B29 triazole bridge, was highly active in binding to both IR isoforms, with a significant preference for IR-B. Our results demonstrate the potential of chemistry-driven modulation of insulin function, also shedding new light on the functional importance of hormone's B-chain C-terminus for its IR-B specificity.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, the Czech Academy of Sciences, v.v.i., Flemingovo n. 2, 166 10 Praha 6, Czech Republic.
authors.forename: Jitka
authors.initials: J
authors.lastname: Viková
authors.affiliation: Institute of Organic Chemistry and Biochemistry, the Czech Academy of Sciences, v.v.i., Flemingovo n. 2, 166 10 Praha 6, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Collinsová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, the Czech Academy of Sciences, v.v.i., Flemingovo n. 2, 166 10 Praha 6, Czech Republic.
authors.forename: Emília
authors.initials: E
authors.lastname: Kletvíková
authors.affiliation: Institute of Organic Chemistry and Biochemistry, the Czech Academy of Sciences, v.v.i., Flemingovo n. 2, 166 10 Praha 6, Czech Republic.
authors.forename: Miloš
authors.initials: M
authors.lastname: Buděšínský
authors.affiliation: Institute of Organic Chemistry and Biochemistry, the Czech Academy of Sciences, v.v.i., Flemingovo n. 2, 166 10 Praha 6, Czech Republic.
authors.forename: Vojtěch
authors.initials: V
authors.lastname: Kaplan
authors.affiliation: Institute of Organic Chemistry and Biochemistry, the Czech Academy of Sciences, v.v.i., Flemingovo n. 2, 166 10 Praha 6, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Žáková
authors.affiliation: Institute of Organic Chemistry and Biochemistry, the Czech Academy of Sciences, v.v.i., Flemingovo n. 2, 166 10 Praha 6, Czech Republic.
authors.forename: Václav
authors.initials: V
authors.lastname: Veverka
authors.affiliation: Institute of Organic Chemistry and Biochemistry, the Czech Academy of Sciences, v.v.i., Flemingovo n. 2, 166 10 Praha 6, Czech Republic.
authors.forename: Rozálie
authors.initials: R
authors.lastname: Hexnerová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, the Czech Academy of Sciences, v.v.i., Flemingovo n. 2, 166 10 Praha 6, Czech Republic.
authors.forename: Roberto J
authors.initials: RJ
authors.lastname: Tarazona Aviñó
authors.affiliation: Institute of Organic Chemistry and Biochemistry, the Czech Academy of Sciences, v.v.i., Flemingovo n. 2, 166 10 Praha 6, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Straková
authors.affiliation: Institute of Organic Chemistry and Biochemistry, the Czech Academy of Sciences, v.v.i., Flemingovo n. 2, 166 10 Praha 6, Czech Republic.
authors.forename: Irena
authors.initials: I
authors.lastname: Selicharová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, the Czech Academy of Sciences, v.v.i., Flemingovo n. 2, 166 10 Praha 6, Czech Republic.
authors.forename: Václav
authors.initials: V
authors.lastname: Vaněk
authors.affiliation: York Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York YO10 5DD, United Kingdom.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Wright
authors.affiliation: York Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York YO10 5DD, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Watson
authors.affiliation: York Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York YO10 5DD, United Kingdom.
authors.forename: Johan P
authors.initials: JP
authors.lastname: Turkenburg
authors.affiliation: York Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York YO10 5DD, United Kingdom.
authors.forename: Andrzej M
authors.initials: AM
authors.lastname: Brzozowski
authors.affiliation: Institute of Organic Chemistry and Biochemistry, the Czech Academy of Sciences, v.v.i., Flemingovo n. 2, 166 10 Praha 6, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Jiráček
mesh_terms: D000480:Alkynes / Q000737:chemistry; D001386:Azides / Q000737:chemistry; D061565:Cycloaddition Reaction; D006801:Humans; D007328:Insulin / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D020033:Protein Isoforms; D055550:Protein Stability; D017526:Receptor, IGF Type 1 / Q000737:chemistry / Q000378:metabolism; D011972:Receptor, Insulin / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000480:Alkynes; D001386:Azides; D007328:Insulin; D020033:Protein Isoforms; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin