5L3N

D11 bound [N29, S39_PQ]-IGF-II

Summary for 5L3N

• Entry DOI: 10.2210/pdb5l3n/pdb
• NMR Information: BMRB: 34002
• Descriptor: Insulin-like growth factor II (1 entity in total)
• Functional Keywords: igf-ii, cell cycle
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 7736.74

Authors

Hexnerova, R. (deposition date: 2016-05-23, release date: 2016-08-10, Last modification date: 2024-11-06)

Primary citation

Hexnerova, R.,Krizkova, K.,Fabry, M.,Sieglova, I.,Kedrova, K.,Collinsova, M.,Ullrichova, P.,Srb, P.,Williams, C.,Crump, M.P.,Tosner, Z.,Jiracek, J.,Veverka, V.,Zakova, L.
Probing Receptor Specificity by Sampling the Conformational Space of the Insulin-like Growth Factor II C-domain.
J.Biol.Chem., 291:21234-21245, 2016

PubMed Abstract: Insulin and insulin-like growth factors I and II are closely related protein hormones. Their distinct evolution has resulted in different yet overlapping biological functions with insulin becoming a key regulator of metabolism, whereas insulin-like growth factors (IGF)-I/II are major growth factors. Insulin and IGFs cross-bind with different affinities to closely related insulin receptor isoforms A and B (IR-A and IR-B) and insulin-like growth factor type I receptor (IGF-1R). Identification of structural determinants in IGFs and insulin that trigger their specific signaling pathways is of increasing importance in designing receptor-specific analogs with potential therapeutic applications. Here, we developed a straightforward protocol for production of recombinant IGF-II and prepared six IGF-II analogs with IGF-I-like mutations. All modified molecules exhibit significantly reduced affinity toward IR-A, particularly the analogs with a Pro-Gln insertion in the C-domain. Moreover, one of the analogs has enhanced binding affinity for IGF-1R due to a synergistic effect of the Pro-Gln insertion and S29N point mutation. Consequently, this analog has almost a 10-fold higher IGF-1R/IR-A binding specificity in comparison with native IGF-II. The established IGF-II purification protocol allowed for cost-effective isotope labeling required for a detailed NMR structural characterization of IGF-II analogs that revealed a link between the altered binding behavior of selected analogs and conformational rearrangement of their C-domains.

PubMed: 27510031
DOI: 10.1074/jbc.M116.741041

Experimental method

SOLUTION NMR