“F1000（Faculty of 1000 Medicine）”又名“千名醫(yī)學(xué)家”,，是由美國(guó)哈佛大學(xué)和英國(guó)劍橋大學(xué)等全世界2500名國(guó)際頂級(jí)醫(yī)學(xué)教授組成的國(guó)際權(quán)威機(jī)構(gòu),。1月，F(xiàn)1000上的兩篇論文引發(fā)了關(guān)于在無(wú)穩(wěn)定結(jié)構(gòu)的情況下,，是否能進(jìn)行蛋白識(shí)別的爭(zhēng)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(shí),，蛋白質(zhì)鏈上相距較遠(yuǎn)的氨基酸殘基之間的物理相互作用較少，在折疊態(tài)時(shí),，則存在很多這樣的長(zhǎng)程特異相互作用,，它們實(shí)際上定義了蛋白質(zhì)的三級(jí)結(jié)構(gòu)。所謂蛋白質(zhì)結(jié)構(gòu)主要是針對(duì)這種長(zhǎng)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(tuán)的相對(duì)位置和取向,，測(cè)定蛋白質(zhì)的空間結(jié)構(gòu)就是要通過(guò)物（化學(xué)）手段確定這些相對(duì)位置和取向。
然而對(duì)于譬如酶作用等方面的蛋白識(shí)別機(jī)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(diǎn)，有助于解析這些問(wèn)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(lái)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(shí)別的鎖鑰模型并不是一個(gè)普遍原理——鎖鑰模型認(rèn)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(shí)候，才能像鑰匙把鎖打開(kāi)一樣,，產(chǎn)生相互作用,。而這項(xiàng)研究的研究人員則認(rèn)為一些蛋白即使沒(méi)有一種嚴(yán)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(rèn)為，機(jī)體細(xì)胞中真實(shí)環(huán)境下的蛋白功能依賴于其結(jié)構(gòu),，并且蛋白識(shí)別需要能相互識(shí)別結(jié)合的互補(bǔ)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(guó)學(xué)院的Michael J.E. Sternberg還指出,，許多蛋白在試管中看起來(lái)好似是無(wú)序的,，但是實(shí)際上，這些蛋白如果和伴體（PWPs）相結(jié)合,，就能與細(xì)胞中其它元件相互作用,，形成有序結(jié)構(gòu)，行使功能,。
對(duì)于這一觀點(diǎn),，第一篇文章的作者Dunker和 Uversky反駁道，普通蛋白和無(wú)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(wú)序的狀態(tài)。而且比較于“等待伴體”,，一些IDPs活動(dòng)性更強(qiáng),，能從一種伴體轉(zhuǎn)向另外一種，并在改變伴體的時(shí)候,，改變其結(jié)構(gòu),。
MRC實(shí)驗(yàn)室的Richard Henderson對(duì)這兩篇文章進(jìn)行了點(diǎn)評(píng)，他表示,，“這兩篇文章都提出了關(guān)于看似天然無(wú)序的蛋白功能的一些觀點(diǎn),，他們有著不同的側(cè)重點(diǎn)，這毫無(wú)疑問(wèn)將促進(jìn)結(jié)構(gòu)生物學(xué)研究實(shí)驗(yàn)和爭(zhēng)論的更深入發(fā)展,。時(shí)間將會(huì)告訴我們,，哪種，或者哪幾種模型才是大自然真實(shí)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.
