美國德州萊斯大學(xué)（Rice University）及Baylor醫(yī)學(xué)院（Baylor college of medicine）的研究人員,，利用數(shù)學(xué)算法與X-ray結(jié)晶學(xué)的信息結(jié)合，破解蛋白質(zhì)結(jié)構(gòu)中會移動的部分結(jié)構(gòu)（moving parts）,，有助于對結(jié)構(gòu)生物學(xué)分類的厘清，并對引起癌癥或其它疾病蛋白質(zhì)的活性區(qū)（active sites）有更多的了解,。此研究發(fā)表于PNAS期刊,。
Jianpeng Ma教授說：「這項技術(shù)對于較大、較復(fù)雜以及有彈性易彎由（flexible）的蛋白質(zhì)結(jié)構(gòu)區(qū)域的精細(xì)化（refinetment）有很大的幫助,。利用數(shù)學(xué)算法及結(jié)晶學(xué)結(jié)果的信息對比,，找到可能的蛋白質(zhì)結(jié)構(gòu)?！乖?jīng)是諾貝爾獎得主的哈佛大學(xué)教授William Lipscomb也表示：「這項研究對于蛋白質(zhì)結(jié)構(gòu)生物學(xué)領(lǐng)域的確是一項重大成就,。」
蛋白質(zhì)是由胺基酸一個一個串起來而形成的分子,，目前的技術(shù)已能將這些胺基酸序列定義出來,，但對于3D結(jié)構(gòu)中較有彈性而會游動的部分，則仍然很難透過結(jié)晶學(xué)的技術(shù)直接解開,，而這部分的蛋白質(zhì)往往又是重要的功能區(qū),，例如：是酵素的催化中心或是訊息蛋白?？康拇a頭。因此,，加速解開此區(qū)域的蛋白質(zhì)結(jié)構(gòu),，對于癌癥或相關(guān)疾病的藥物設(shè)計可說具有重要的意義。
Ma 教授說：「這些年來若沒Billy Poon以及Xiaorui Chen這兩位堅忍不拔的學(xué)生,，日以繼夜的配戴著特殊護(hù)目鏡焚膏繼晷的進(jìn)行研究,，不會有此革命性的研究出現(xiàn)。這個方法能改善許多蛋白質(zhì)3D結(jié)構(gòu)的譯碼,，而事實上已證明此方法的適用性極高,，并已解決許多膜蛋白（membrane proteins）結(jié)構(gòu)的問題?！?/p>
（編譯/陳瑞娟） (資料來源 : Bio.com)
原始出處：
Published online before print April 30, 2007, 10.1073/pnas.0701204104
PNAS | May 8, 2007 | vol. 104 | no. 19 | 7869-7874
Normal mode refinement of anisotropic thermal parameters for a supramolecular complex at 3.42-Å crystallographic resolution
Billy K. Poon, Xiaorui Chen, Mingyang Lu, Nand K. Vyas, Florante A. Quiocho, Qinghua Wang, and Jianpeng Ma,,,¶
Department of Bioengineering, Rice University, Houston, TX 77005; Graduate Program of Structural and Computational Biology and Molecular Biophysics and Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, BCM-125, Houston, TX 77030
Edited by William N. Lipscomb, Harvard University, Cambridge, MA, and approved March 27, 2007 (received for review February 8, 2007)
Abstract
Here we report a normal-mode-based protocol for modeling anisotropic thermal motions of proteins in x-ray crystallographic refinement. The foundation for this protocol is a recently developed elastic normal mode analysis that produces much more accurate eigenvectors without the tip effect. The effectiveness of the procedure is demonstrated on the refinement of a 3.42-Å structure of formiminotransferase cyclodeaminase, a 0.5-MDa homooctameric enzyme. Using an order of magnitude fewer adjustable thermal parameters than the conventional isotropic refinement, this protocol resulted in a decrease of the values of Rcryst and Rfree and improvements of the density map. Several poorly resolved regions in the original isotropically refined structure became clearer so that missing side chains were fitted easily and mistraced backbone was corrected. Moreover, the distribution of anisotropic thermal ellipsoids revealed functionally important structure flexibility. This normal-mode-based refinement is an effective way of describing anisotropic thermal motions in x-ray structures and is particularly attractive for the refinement of very large and flexible supramolecular complexes at moderate resolutions.
anisotropic temperature factor | conformational flexibility | elastic normal mode analysis | tip effect | x-ray crystallographic refinement
Fig. 1. Structure of FTCD. (a) The square doughnut structure of an FTCD octamer. Two subunits are shown in red and blue, respectively. (b) The subunit structure of ligand-free FTCD. Backbone trace color ramped from the N terminus to the C terminus. (c) Superposition of the FT domain of human ligand-free FTCD (red) with the structure of the same domain in isolation (cyan) with the product analog, folinic acid (CPK mode), bound in the groove. (d) Rainbow-colored isotropic B factor in the original model. The hotter the color, the larger the B factors. The high flexibility of the N-subdomain, the linker region, and the lower half of the CD domain is evident.
