The collagen binding integrin α2β1 plays a crucial role in hemostasis, fibrosis, and cancer progression amongst others. It is specifically inhibited by rhodocetin (RC), a C-type lectin-related protein (CLRP) found in Malayan pit viper (Calloselasma rhodostoma) venom. The structure of RC alone reveals a heterotetramer arranged as an αβ and γδ subunit in a cruciform shape. RC specifically binds to the collagen binding A-domain of the integrin α2 subunit, thereby blocking collagen-induced platelet aggregation. However, until now, the molecular basis for this interaction has remained unclear. Here, we present the molecular structure of the RCγδ-α2A complex solved to 3.0 Å resolution. Our findings show that RC undergoes a dramatic structural reorganization upon binding to α2β1 integrin. Besides the release of the nonbinding RCαβ tandem, the RCγ subunit interacts with loop 2 of the α2A domain as result of a dramatic conformational change. The RCδ subunit contacts the integrin α2A domain in the “closed” conformation through its helix C. Combined with epitope-mapped antibodies, conformationally locked α2A domain mutants, point mutations within the α2A loop 2, and chemical modifications of the purified toxin protein, this molecular structure of RCγδ-α2A complex explains the inhibitory mechanism and specificity of RC for α2β1 integrin.

胶原结合整联蛋白α2β1在止血，纤维化和癌症进展等方面起着至关重要的作用。它受到马来亚蛇（Calloselasma rhodostoma）中发现的一种C型凝集素相关蛋白（CLRP）视紫红质（RC）的特异性抑制。）毒液。单独的RC结构揭示出异四聚体以十字形排列为αβ和γδ亚基。RC特异性结合整联蛋白α2亚基的胶原蛋白结合A结构域，从而阻止胶原蛋白诱导的血小板聚集。然而，直到现在，这种相互作用的分子基础仍不清楚。在这里，我们介绍了解析为3.0Å分辨率的RCγδ-α2A配合物的分子结构。我们的发现表明，RC与α2β1整联蛋白结合后会发生剧烈的结构重组。除了释放非结合性RCαβ串联外，RCγ亚基还因构象变化而与α2A结构域的环2相互作用。RCδ亚基通过其螺旋C以“封闭”构型接触整联蛋白α2A结构域。结合表位映射的抗体，