REFINED STRUCTURE OF THE HUMAN HISTOCOMPATIBILITY ANTIGEN HLA-A2 AT 2.6A RESOLUTION
REFINED STRUCTURE OF THE HUMAN HISTOCOMPATIBILITY ANTIGEN HLA-A2 AT 2.6A RESOLUTION
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DOI：
10.1016/0022-2836(91)90567-p
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发表时间：
1991-05-20
影响因子：
5.6
通讯作者：
WILEY, DC
中科院分区：
文献类型：
--
作者：
SAPER, MA;BJORKMAN, PJ;WILEY, DC
人类组织相容性抗原HLA-A2的三维结构在3.5 μ m分辨率下通过两种晶体形式的同晶置换和迭代实空间平均的组合来确定。单斜晶型现在已经通过最小二乘法进行了修正，对于6 - 2.6 μ m分辨率的数据，R因子为0.169。异源二聚体中发现的结构相似结构域的叠加，α 1与α 2，α 3与β 2 m，以及后一对与祖先相关的免疫球蛋白恒定结构域，表明差异主要在转角区域。分析了α 1和α 2结构域的结构特征，如有助于稳定性的保守盐桥，与其他结构域形成接触的特异性环，以及由八链β折叠顶部的两个相邻螺旋区域形成的抗原结合沟。详细描述了结构域之间的界面，特别是β 2 m与HLA重链之间的界面，这些界面可能参与β 2 m交换和异源二聚体组装。对结合沟的详细检查证实，在小鼠和人类等位基因中最具多态性的溶剂可及氨基酸侧链填充了结合沟的中心和最宽部分，而保守的侧链聚集在凹槽的较窄端。抗原结合沟中的六个口袋或亚位点具有不同的形状和组成，似乎适合于结合来自抗原肽的侧链。其中三个口袋主要含有非极性原子，而其他口袋，特别是位于凹槽末端的口袋，则含有极性原子簇，这些原子簇靠近结合位点的“额外”电子密度。
The three-dimensional structure of the human histocompatibility antigen HLA-A2 was determined at 3.5 Å resolution by a combination of isomorphous replacement and iterative real-space averaging of two crystal forms. The monoclinic crystal form has now been refined by least-squares methods to anR-factor of 0.169 for data from 6 to 2.6 Å resolution.A superposition of the structurally similar domains found in the heterodimer,α1ontoα2andα3ontoβ2m, as well as the latter pair onto the ancestrally related immunoglobulin constant domain, reveals that differences are mainly in the turn regions. Structural features of theα1andα2domains, such as conserved salt-bridges that contribute to stability, specific loops that form contacts with other domains, and the antigen-binding groove formed from two adjacent helical regions on top of an eight-stranded β-sheet, are analyzed. The interfaces between the domains, especially those betweenβ2m and the HLA heavy chain presumably involved inβ2m exchange and heterodimer assembly, are described in detail.A detailed examination of the binding groove confirms that the solvent-accessible amino acid side-chains that are most polymorphic in mouse and human alleles fill up the central and widest portion of the binding groove, while conserved side-chains are clustered at the narrower ends of the groove. Six pockets or sub-sites in the antigen-binding groove, of diverse shape and composition, appear suited for binding side-chains from antigenic peptides. Three pockets contain predominantly non-polar atoms; but others, especially those at the extreme ends of the groove, have clusters of polar atoms in close proximity to the “extra” electron density in the binding site.A possible role forβ2m in stabilizing permissible peptide complexes during folding and assembly is presented.