科學(xué)家發(fā)現(xiàn)了一種讓胰島素活化必需的關(guān)鍵結(jié)構(gòu)變化,，這可能帶來改良的糖尿病療法,。胰島素調(diào)控血糖濃度，而且對脂肪和蛋白質(zhì)代謝具有廣泛影響,；這種小激素的濃度減少或細胞對其存在的不敏感通常會導(dǎo)致糖尿病——全球?qū)⒔?%的人口受該病的影響,。胰島素由AB兩個肽鏈組成，由分子內(nèi)鍵將其穩(wěn)定,。
Andrzej Brzozowski及其同事設(shè)計并分析了具有高度活性的胰島素相似體的結(jié)構(gòu),，從而確定這種激素在它的受體上的活化形態(tài)的準確結(jié)構(gòu)，這在很大程度上是未知的,。這組科學(xué)家發(fā)現(xiàn),， 縮短這種蛋白質(zhì)B鏈上的一種蛋白質(zhì)殘基會導(dǎo)致胰島素從活化轉(zhuǎn)向不活化,。這組科學(xué)家報告說,，這種蛋白質(zhì)改變帶來的構(gòu)象變化顯示了去掉的氨基酸涉及了胰島素與其受體的結(jié)合。這組作者說,，這些氨基酸可能為實驗方法提供結(jié)構(gòu)細節(jié),，從而設(shè)計出有效治療糖尿病的配合物。（生物谷Bioon.com）
生物谷推薦原始出處：
PNAS January 25, 2010, doi: 10.1073/pnas.0911785107
Implications for the active form of human insulin based on the structural convergence of highly active hormone analogues
Ji?í Jirá?eka, Lenka ?ákováa, Emília Antolíkováa, Christopher J. Watsonb, Johan P. Turkenburgb, Guy G. Dodsonb, and Andrzej M. Brzozowskib,1
aInstitute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic and
bYork Structural Biology Laboratory, Department of Chemistry, The University of York, Heslington, York, YO10 5YW, United Kingdom
Insulin is a key protein hormone that regulates blood glucose levels and, thus, has widespread impact on lipid and protein metabolism. Insulin action is manifested through binding of its monomeric form to the Insulin Receptor (IR). At present, however, our knowledge about the structural behavior of insulin is based upon inactive, multimeric, and storage-like states. The active monomeric structure, when in complex with the receptor, must be different as the residues crucial for the interactions are buried within the multimeric forms. Although the exact nature of the insulin’s induced-fit is unknown, there is strong evidence that the C-terminal part of the B-chain is a dynamic element in insulin activation and receptor binding. Here, we present the design and analysis of highly active (200–500%) insulin analogues that are truncated at residue 26 of the B-chain (B26). They show a structural convergence in the form of a new β-turn at B24-B26. We propose that the key element in insulin’s transition, from an inactive to an active state, may be the formation of the β-turn at B24-B26 associated with a trans to cis isomerisation at the B25-B26 peptide bond. Here, this turn is achieved with N-methylated L-amino acids adjacent to the trans to cis switch at the B25-B26 peptide bond or by the insertion of certain D-amino acids at B26. The resultant conformational changes unmask previously buried amino acids that are implicated in IR binding and provide structural details for new approaches in rational design of ligands effective in combating diabetes.
