6rva | pdb_00006rva
STRUCTURE OF [ASP58]-IGF-I ANALOGUE
Structural highlights
Disease[IGF1_HUMAN] Defects in IGF1 are the cause of insulin-like growth factor I deficiency (IGF1 deficiency) [MIM:608747]. IGF1 deficiency is an autosomal recessive disorder characterized by growth retardation, sensorineural deafness and mental retardation. Function[IGF1_HUMAN] The insulin-like growth factors, isolated from plasma, are structurally and functionally related to insulin but have a much higher growth-promoting activity. May be a physiological regulator of [1-14C]-2-deoxy-D-glucose (2DG) transport and glycogen synthesis in osteoblasts. Stimulates glucose transport in rat bone-derived osteoblastic (PyMS) cells and is effective at much lower concentrations than insulin, not only regarding glycogen and DNA synthesis but also with regard to enhancing glucose uptake.[1] Publication Abstract from PubMedInformation on how insulin and insulin-like growth factors 1 and 2 (IGF-1 and -2) activate insulin receptors (IR-A and -B) and the IGF-1 receptor (IGF-1R) is crucial for understanding the difference in the biological activities of these peptide hormones. Cryo-EM studies have revealed that insulin uses its binding sites 1 and 2 to interact with IR-A and have identified several critical residues in binding site 2. However, mutagenesis studies suggest that IleA10, SerA12, LeuA13, and GluA17 also belong to insulin's site 2. Here, to resolve this discrepancy, we mutated these insulin residues and the equivalent residues in IGFs. Our findings revealed that equivalent mutations in the hormones can result in differential biological effects and that these effects can be receptor-specific. We noted that the insulin positions A10 and A17 are important for its binding to IR-A and IR-B and IGF-1R and that A13 is important only for IR-A and IR-B binding. The IGF-1/IGF-2 positions 51/50 and 54/53 did not appear to play critical roles in receptor binding, but mutations at IGF-1 position 58 and IGF-2 position 57 affected the binding. We propose that IGF-1 Glu58 interacts with IGF-1R Arg704 and belongs to IGF-1 site 1, a finding supported by the NMR structure of the less active Asp58-IGF-1 variant. Computational analyses indicated that the aforementioned mutations can affect internal insulin dynamics and inhibit adoption of a receptor-bound conformation, important for binding to receptor site 1. We provide a molecular model and alternative hypotheses for how the mutated insulin residues affect activity. Mutations at hypothetical binding site 2 in insulin and insulin-like growth factors 1 and 2 result in receptor- and hormone-specific responses.,Machackova K, Mlcochova K, Potalitsyn P, Hankova K, Socha O, Budesinsky M, Muzdalo A, Lepsik M, Cernekova M, Radosavljevic J, Fabry M, Mitrova K, Chrudinova M, Lin J, Yurenko Y, Hobza P, Selicharova I, Akova L, Jiracek J J Biol Chem. 2019 Sep 26. pii: RA119.010072. doi: 10.1074/jbc.RA119.010072. PMID:31558604[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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