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Publication Abstract from PubMed

The crystal structures of free T-state and R-state glycogen phosphorylase (GP) and of R-state GP in complex with the allosteric activators IMP and AMP are reported at improved resolution. GP is a validated pharmaceutical target for the development of antihyperglycaemic agents, and the reported structures may have a significant impact on structure-based drug-design efforts. Comparisons with previously reported structures at lower resolution reveal the detailed conformation of important structural features in the allosteric transition of GP from the T-state to the R-state. The conformation of the N-terminal segment (residues 7-17), the position of which was not located in previous T-state structures, was revealed to form an alpha-helix (now termed alpha0). The conformation of this segment (which contains Ser14, phosphorylation of which leads to the activation of GP) is significantly different between the T-state and the R-state, pointing in opposite directions. In the T-state it is packed between helices alpha4 and alpha16 (residues 104-115 and 497-508, respectively), while in the R-state it is packed against helix alpha1 (residues 22'-38') and towards the loop connecting helices alpha4' and alpha5' of the neighbouring subunit. The allosteric binding site where AMP and IMP bind is formed by the ordering of a loop (residues 313-326) which is disordered in the free structure, and adopts a conformation dictated mainly by the type of nucleotide that binds at this site.

Glycogen phosphorylase revisited: extending the resolution of the R- and T-state structures of the free enzyme and in complex with allosteric activators.,Leonidas DD, Zographos SE, Tsitsanou KE, Skamnaki VT, Stravodimos G, Kyriakis E Acta Crystallogr F Struct Biol Commun. 2021 Sep 1;77(Pt 9):303-311. doi:, 10.1107/S2053230X21008542. Epub 2021 Aug 26. PMID:34473107^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.