Complex structure of engineered modular domains defining molecular interaction between ICAM-1 and integrin LFA-1.
Complex structure of engineered modular domains defining molecular interaction between ICAM-1 and integrin LFA-1.
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DOI：
10.1371/journal.pone.0044124
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Jin MM
中科院分区：
文献类型：
--
作者：
Kang S;Kim CU;Gu X;Owens RM;van Rijn SJ;Boonyaleepun V;Mao Y;Springer TA;Jin MM
整合素LFA-1 （αL - β2）与ICAM-1的分子间接触仅来源于整合素αL I结构域和ICAM-1的第一结构域（D1）。本研究提出了αL I结构域与ICAM-1 D1工程配合物的晶体结构。以前，我们通过定向进化方法鉴定的点突变设计了高亲和力的I结构域。为了检测αL I结构域在c端α7-螺旋（变构位点）和金属离子依赖的粘附位点（活性位点）之间的变构，我们选择了一个高亲和变异，其突变不会直接影响α7-螺旋的位置或活性位点。在我们的晶体中，αL I结构域被发现与D1具有高亲和力构象，其α7-螺旋向下移位远离结合界面，概括了目前对I结构域的变构及其与信号传导中邻近整合素结构域的联系的理解。为了使ICAM-1的可溶性D1能够自己折叠，我们还设计了D1通过突变发挥功能，这些突变被发现可以将溶剂排除核心中的氢键网络转化为vdW接触。工程型D1的β-三明治折叠的主链结构和I结构域结合的表位与野生型D1基本相同。在与人鼻病毒（HRV）相互作用的n端区域的环中发现了工程D1的大多数偏差。在工程D1中发现的结构偏差总体上与先前观察到的工程D1的功能一致，即与αL I结构域完全结合，但与HRV的相互作用减少。
Intermolecular contacts between integrin LFA-1 (αLβ2) and ICAM-1 derive solely from the integrin αL I domain and the first domain (D1) of ICAM-1. This study presents a crystal structure of the engineered complex of the αL I domain and ICAM-1 D1. Previously, we engineered the I domain for high affinity by point mutations that were identified by a directed evolution approach. In order to examine αL I domain allostery between the C-terminal α7-helix (allosteric site) and the metal-ion dependent adhesion site (active site), we have chosen a high affinity variant without mutations directly influencing either the position of the α7-helix or the active sites. In our crystal, the αL I domain was found to have a high affinity conformation to D1 with its α7-helix displaced downward away from the binding interface, recapitulating a current understanding of the allostery in the I domain and its linkage to neighboring domains of integrins in signaling. To enable soluble D1 of ICAM-1 to fold on its own, we also engineered D1 to be functional by mutations, which were found to be those that would convert hydrogen bond networks in the solvent-excluded core into vdW contacts. The backbone structure of the β-sandwich fold and the epitope for I domain binding of the engineered D1 were essentially identical to those of wild-type D1. Most deviations in engineered D1 were found in the loops at the N-terminal region that interacts with human rhinovirus (HRV). Structural deviation found in engineered D1 was overall in agreement with the function of engineered D1 observed previously, i.e., full capacity binding to αL I domain but reduced interaction with HRV.
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影响因子：
30.5
作者：
Ostermann, G;Weber, KSC;Weber, C
通讯作者：
Weber, C
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.90.2.507
发表时间：
1993-01-15
影响因子：
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作者：
OLSON, NH;KOLATKAR, PR;ROSSMANN, MG
通讯作者：
ROSSMANN, MG
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH