2m2n

Structure of [L-HisB24] insulin analogue at pH 8.0Structure of [L-HisB24] insulin analogue at pH 8.0

Structural highlights 2m2n is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Solution NMR, 30 models Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Despite the recent first insight into the insulin-insulin receptor complex, the structural role of the C-terminus of the B-chain of insulin in this assembly remains unresolved. Previous studies have suggested that this part of insulin must rearrange to reveal amino acids crucial for interaction with the receptor. The role of the invariant PheB24, one of the key residues of the hormone, in this process remains unclear. For example, the B24 site functionally tolerates substitutions to D-amino acids but not to L-amino acids. Here, we prepared and characterized a series of B24-modified insulin analogues, determining also the structures of [D-HisB24]-insulin and [HisB24]-insulin. The inactive [HisB24]-insulin molecule is remarkably rigid due to a tight accommodation of the L-His side chain in the B24-binding pocket that results in the stronger tethering of B25-B28 residues to the protein core. In contrast, the highly active [D-HisB24]-insulin is more flexible, and the reverse chirality of the B24Calpha atom swayed the D-HisB24 side chain into the solvent. Furthermore, the pocket vacated by PheB24 is filled by PheB25, which mimics the PheB24 side and main chains. The B25-->B24 downshift results in a subsequent downshift of TyrB26 into the B25 site and the departure of B26-B30 residues away from the insulin core. Our data indicate the importance of the aromatic L-amino acid at the B24 site and the structural invariance/integrity of this position for an effective binding of insulin to its receptor. Moreover, they also suggest limited, B25-B30 only, unfolding of the C-terminus of the B-chain upon insulin activation. Structural Integrity of the B24 Site in Human Insulin is Important for Hormone Functionality.,Zakova L, Kletvikova E, Veverka V, Lepsik M, Watson CJ, Turkenburg JP, Jiracek J, Brzozowski AM J Biol Chem. 2013 Feb 27. PMID:23447530 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Insulin 3D Structures

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