5BQQ

Human insulin with intra-chain chemical crosslink between modified B27 and B30

Summary for 5BQQ

• Entry DOI: 10.2210/pdb5bqq/pdb
• Descriptor: Insulin, PHENOL, ZINC ION, ... (6 entities in total)
• Functional Keywords: chemical crosslink, b24-b29, specificity, hormone
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted: P01308 P01308
• Total number of polymer chains: 12
• Total formula weight: 35826.28

Authors

Brzozowski, A.M.,Turkenburg, J.P.,Jiracek, J.,Zakova, L. (deposition date: 2015-05-29, release date: 2016-02-03, Last modification date: 2024-01-10)

Primary citation

Vikova, J.,Collinsova, M.,Kletvikova, E.,Budesinsky, M.,Kaplan, V.,Zakova, L.,Veverka, V.,Hexnerova, R.,Avino, R.J.,Strakova, J.,Selicharova, I.,Vanek, V.,Wright, D.W.,Watson, C.J.,Turkenburg, J.P.,Brzozowski, A.M.,Jiracek, J.
Rational steering of insulin binding specificity by intra-chain chemical crosslinking.
Sci Rep, 6:19431-19431, 2016

PubMed 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.

PubMed: 26792393
DOI: 10.1038/srep19431

Experimental method

X-RAY DIFFRACTION (1.54 Å)