“F1000（Faculty of 1000 Medicine）”又名“千名醫(yī)學(xué)家”,，是由美國哈佛大學(xué)和英國劍橋大學(xué)等全世界2500名國際頂級醫(yī)學(xué)教授組成的國際權(quán)威機構(gòu)。1月,，F(xiàn)1000上的兩篇論文引發(fā)了關(guān)于在無穩(wěn)定結(jié)構(gòu)的情況下,，是否能進行蛋白識別的爭論。
蛋白質(zhì)結(jié)構(gòu)是三維的空間結(jié)構(gòu),，在去折疊態(tài)時,，蛋白質(zhì)鏈上相距較遠的氨基酸殘基之間的物理相互作用較少，在折疊態(tài)時,，則存在很多這樣的長程特異相互作用,，它們實際上定義了蛋白質(zhì)的三級結(jié)構(gòu)。所謂蛋白質(zhì)結(jié)構(gòu)主要是針對這種長程的特異相互作用而言,。它們本質(zhì)上是三維空間中原子和原子基團的相對位置和取向,，測定蛋白質(zhì)的空間結(jié)構(gòu)就是要通過物（化學(xué)）手段確定這些相對位置和取向。
然而對于譬如酶作用等方面的蛋白識別機理而言,，仍然存在一些謎題有待解決,，這兩篇文章提出了兩種不同的觀點，有助于解析這些問題,。
在第一篇文章：“The case for intrinsically disordered proteins playing contributory roles in molecular recognition without a stable 3D structure”中,，來自印第安納大學(xué)醫(yī)學(xué)院的Keith Dunker和俄羅斯科學(xué)院的Vladimir N. Uversky提出，蛋白識別的鎖鑰模型并不是一個普遍原理——鎖鑰模型認為酶和底物的關(guān)系如同鎖和鑰匙的關(guān)系一樣,，酶分子就像一把鎖,，而底物像是一把鑰匙,，當(dāng)酶和底物的空間構(gòu)象正好能完全彌合的時候，才能像鑰匙把鎖打開一樣,，產(chǎn)生相互作用,。而這項研究的研究人員則認為一些蛋白即使沒有一種嚴格的結(jié)構(gòu)，比如天然失序蛋白（IDPs）也具有功能,。
相反,，第二篇文章（Protein flexibility, not disorder, is intrinsic to molecular recognition）則認為，機體細胞中真實環(huán)境下的蛋白功能依賴于其結(jié)構(gòu),，并且蛋白識別需要能相互識別結(jié)合的互補結(jié)構(gòu),。
而且文章作者：巴黎第十一大學(xué)的Jo?l Janin，和倫敦帝國學(xué)院的Michael J.E. Sternberg還指出,，許多蛋白在試管中看起來好似是無序的,，但是實際上，這些蛋白如果和伴體（PWPs）相結(jié)合,，就能與細胞中其它元件相互作用,，形成有序結(jié)構(gòu)，行使功能,。
對于這一觀點,，第一篇文章的作者Dunker和 Uversky反駁道，普通蛋白和無序蛋白IDPs之間的主要差別,，在于前者先折疊后結(jié)合到伴體上,，而后者則是與伴體結(jié)合后才改變其無序的狀態(tài)。而且比較于“等待伴體”,，一些IDPs活動性更強,，能從一種伴體轉(zhuǎn)向另外一種，并在改變伴體的時候,，改變其結(jié)構(gòu),。
MRC實驗室的Richard Henderson對這兩篇文章進行了點評，他表示,，“這兩篇文章都提出了關(guān)于看似天然無序的蛋白功能的一些觀點，他們有著不同的側(cè)重點,，這毫無疑問將促進結(jié)構(gòu)生物學(xué)研究實驗和爭論的更深入發(fā)展,。時間將會告訴我們，哪種,，或者哪幾種模型才是大自然真實的做法,。”(生物谷Bioon.com)
doi: 10.3410/B5-2
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Protein flexibility, not disorder, is intrinsic to molecular recognition
Joël Janin1 and Michael J.E. Sternberg2
An ‘intrinsically disordered protein’ (IDP) is assumed to be unfolded in the cell and perform its biological function in that state. We contend that most intrinsically disordered proteins are in fact proteins waiting for a partner (PWPs), parts of a multi-component complex that do not fold correctly in the absence of other components. Flexibility, not disorder, is an intrinsic property of proteins, exemplified by X-ray structures of many enzymes and protein-protein complexes. Disorder is often observed with purified proteins in vitro and sometimes also in crystals, where it is difficult to distinguish from flexibility. In the crowded environment of the cell, disorder is not compatible with the known mechanisms of protein-protein recognition, and, foremost, with its specificity. The self-assembly of multi-component complexes may, nevertheless, involve the specific recognition of nascent polypeptide chains that are incompletely folded, but then disorder is transient, and it must remain under the control of molecular chaperones and of the quality control apparatus that obviates the toxic effects it can have on the cell.
doi: 10.3410/B5-1
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The case for intrinsically disordered proteins playing contributory roles in molecular recognition without a stable 3D structure
Vladimir N. Uversky1,2 and A. Keith Dunker1
The classical ‘lock-and-key’ and ‘induced-fit’ mechanisms for binding both originated in attempts to explain features of enzyme catalysis. For both of these mechanisms and for their recent refinements, enzyme catalysis requires exquisite spatial and electronic complementarity between the substrate and the catalyst. Thus, binding models derived from models originally based on catalysis will be highly biased towards mechanisms that utilize structural complementarity. If mere binding without catalysis is the endpoint, then the structural requirements for the interaction become much more relaxed. Recent observations on specific examples suggest that this relaxation can reach an extreme lack of specific 3D structure, leading to molecular recognition with biological consequences that depend not only upon structural and electrostatic complementarity between the binding partners but also upon kinetic, entropic, and generalized electrostatic effects. In addition to this discussion of binding without fixed structure, examples in which unstructured regions carry out important biological functions not involving molecular recognition will also be discussed. Finally, we discuss whether ‘intrinsically disordered protein’ (IDP) represents a useful new concept.
