CRYSTAL-STRUCTURE OF AN H-2K(B)-OVALBUMIN PEPTIDE COMPLEX REVEALS THE INTERPLAY OF PRIMARY AND SECONDARY ANCHOR POSITIONS IN THE MAJOR HISTOCOMPATIBILITY COMPLEX BINDING GROOVE
CRYSTAL-STRUCTURE OF AN H-2K(B)-OVALBUMIN PEPTIDE COMPLEX REVEALS THE INTERPLAY OF PRIMARY AND SECONDARY ANCHOR POSITIONS IN THE MAJOR HISTOCOMPATIBILITY COMPLEX BINDING GROOVE
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DOI：
10.1073/pnas.92.7.2479
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发表时间：
1995-03-28
影响因子：
11.1
通讯作者：
WILSON, IA
中科院分区：
文献类型：
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作者：
FREMONT, DH;STURA, EA;WILSON, IA
对主要组织相容性复合体（MHC）I类分子天然呈递的肽段进行的序列分析揭示了等位基因特异性基序，其中肽段长度以及在某些位置观察到的残基受到限制。然而，含有标准基序的肽段往往无法高亲和力结合或形成生理稳定的复合物。在此，我们展示了来自卵清蛋白的一个特征明确的抗原肽[OVA - 8，卵清蛋白 -（257 - 264），SIINFEKL]与小鼠MHC I类H - 2K(b)分子形成的复合物在2.5埃分辨率下的晶体结构。疏水性肽段残基Ile - P2和Phe - P5紧密堆积在结合口袋B和C中，这表明肽段锚定（P5）和二级锚定（P2）残基的相互作用能够使这些位置上的偏好序列相互关联。与H - 2K(b)分别和肽段VSV - 8（RGYVYQGL）以及SEV - 9（FAPGNYPAL）形成的复合物的晶体结构进行比较，在这些复合物中一个Tyr残基被用作C口袋锚定，结果显示，如果P2侧链尺寸较大，结合在B口袋中并介导来自埋藏的锚定羟基的氢键的保守水分子就无法处于相同位置。基于这一结构证据，H - 2K(b)至少有两个亚基序：一个在P5（对于九肽为P6）是Tyr且在P2是一个小残基（即Ala或Gly），另一个在P5是Phe且在P2是一个中等大小的疏水性残基（即Ile）。从MHC肽段结合的晶体学和免疫学研究中解读这些二级亚基序应该会提高T细胞表位预测的准确性。
Sequence analysis of peptides naturally presented by major histocompatibility complex (MHC) class I molecules has revealed allele-specific motifs in which the peptide length and the residues observed at certain positions are restricted. Nevertheless, peptides containing the standard motif often fail to bind with high affinity or form physiologically stable complexes. Here we present the crystal structure of a well-characterized antigenic peptide from ovalbumin [OVA-8, ovalbumin-(257-264), SIINFEKL] in complex with the murine MHC class I H-2K(b) molecule at 2.5-Angstrom resolution, Hydrophobic peptide residues Ile-P2 and Phe-PS are packed closely together into binding pockets B and C, suggesting that the interplay of peptide anchor (P5) and secondary anchor (P2) residues can couple the preferred sequences at these positions, Comparison with the crystal structures of H-2K(b) in complex with peptides VSV-8 (RGYVYQGL) and SEV-9 (FAPGNYPAL), where a Tyr residue is used as the C pocket anchor, reveals that the conserved water molecule that binds into the B pocket and mediates hydrogen bonding from the buried anchor hydroxyl group could not be likewise positioned if the P2 side chain were of significant size, Based on this structural evidence, H-2K(b) has at least two submotifs: one with Tyr at P5 (or P6 for nonamer peptides) and a small residue at P2 (i.e., Ala or Gly) and another with Phe at P5 and a medium-sized hydrophobic residue at P2 (i,e,, Ile). Deciphering of these secondary submotifs from both crystallographic and immunological studies of MHC peptide binding should increase the accuracy of T-cell epitope prediction.