Molecular dissection of the CD2-CD58 counter-receptor interface identifies CD2 Tyr86 and CD58 Lys34 residues as the functional "hot spot"
Molecular dissection of the CD2-CD58 counter-receptor interface identifies CD2 Tyr86 and CD58 Lys34 residues as the functional "hot spot"
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DOI：
10.1006/jmbi.2001.4980
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发表时间：
2001-09-28
影响因子：
5.6
通讯作者：
Reinherz, EL
中科院分区：
文献类型：
--
作者：
Kim, M;Sun, ZYJ;Reinherz, EL
异嗜性 CD2-CD58 粘附界面包含交指残基，可赋予高特异性和快速结合动力学。为了定义这种反受体相互作用的热点，我们表征了 CD2 粘附结构域变体，其中包含中央 Tyr86 或形成盐键/氢键的每个氨基酸残基的单一突变。通过等温滴定量热法测量，C 链上的 D31、D32 和 K34 以及 C' 链上的 K43 和 R48 处的丙氨酸突变使 CD58 的亲和力降低了 47-127 倍。 Y86A 突变体将亲和力降低了近 1000 倍，而 Y86F 实际上没有影响，这强调了苯环而不是羟基部分的重要性。 CD2CD58晶体结构提供了该kev功能表位的详细视图：CD2D31和D32定向CD58Kj4的侧链，使得CD2Y86与CD2Y86和CD58F46之间的CD58K34的延伸脂肪族组分进行疏水接触。这一热点的阐明为免疫抑制化合物的合理设计提供了新的目标，并为其他受体提供了通用的方法。 (C) 2001 年学术出版社。
The heterophilic CD2-CD58 adhesion interface contains interdigitating residues that impart high specificity and rapid binding kinetics. To define the hot spot of this counter-receptor interaction, we characterized CD2 adhesion domain variants harboring a single mutation of the central Tyr86 or of each amino acid residue forming a salt link/hydrogen bond. Alanine mutations at D31, D32 and K34 on the C strand and K43 and R48 on the C' strand reduce affinity for CD58 by 47-127-fold as measured by isothermal titration calorimetry. The Y86A mutant reduces affinity by similar to 1000-fold, whereas Y86F is virtually without effect, underscoring the importance of the phenyl ring rather than the hydroxyl moiety. The CD2CD58 crystal structure offers a detailed view of this kev functional epitope: CD2 D31 and D32 orient the side-chain of CD58 Kj4 such that CD2 Y86 makes hydrophobic contact with the extended aliphatic component of CD58 K34 between CD2 Y86 and CD58 F46. The elucidation of this hot spot provides a new target for rational design of immunosuppressive compounds and suggests a general approach for other receptors. (C) 2001 Academic Press.