Structure of conkunitzin-S1, a neurotoxin and Kunitz-fold disulfide variant from cone snail
Structure of conkunitzin-S1, a neurotoxin and Kunitz-fold disulfide variant from cone snail
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DOI：
10.1107/s0907444906021122
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发表时间：
2006-09-01
影响因子：
2.2
通讯作者：
Horvath, Martin P.
中科院分区：
文献类型：
--
作者：
Dy, Catherine Y.;Buczek, Pawel;Horvath, Martin P.
锥螺（Conus）是捕食性海洋软体动物，其毒液含有50-200种神经毒性多肽。这些多肽中的大多数是小的富含二硫化物的芋螺毒素，其可以根据其各自的离子通道靶标和半胱氨酸-半胱氨酸二硫化物的模式分类为家族。Conkunitzin-S1是从C. striatus venom）是新定义的芋螺毒素家族的成员，其与Kunitz折叠蛋白如α-树枝毒素和牛胰蛋白酶抑制剂（BPTI）具有序列同源性。虽然conkunitzin-S1和α-树毒素在氨基酸序列上有42%的相同性，但conkunitzin-S1只有通常在Kunitz蛋白中发现的六个半胱氨酸中的四个。本文报道了Conkunitzin-S1的晶体结构。Conkunitzin-S1采用典型的3（10）-beta-beta-alpha Kunitz折叠，并具有额外的独特结构特征，包括两个完全掩埋的水分子。的晶体结构，虽然完全符合以前报道的NMR距离限制，提供了更大程度的原子坐标的精度，特别是对于S原子和埋溶剂分子。在其他Kunitz蛋白中通常由半胱氨酸II和IV交联的区域保留了与在α-树毒素和BPTI中发现的那些相当的氢键和货车范德华相互作用的网络。在conkunitzin-S1中，甘氨酸占据了通常为半胱氨酸II保留的序列位置，并且甘氨酸的特殊空间性质允许与取代半胱氨酸IV的谷氨酰胺残基进行额外的货车范德华接触。因此，进化通过增强和优化较弱但有效的非共价相互作用来支付失去二硫键的代价。
Cone snails (Conus) are predatory marine mollusks that immobilize prey with venom containing 50-200 neurotoxic polypeptides. Most of these polypeptides are small disulfide-rich conotoxins that can be classified into families according to their respective ion-channel targets and patterns of cysteine-cysteine disulfides. Conkunitzin-S1, a potassium-channel pore-blocking toxin isolated from C. striatus venom, is a member of a newly defined conotoxin family with sequence homology to Kunitz-fold proteins such as alpha-dendrotoxin and bovine pancreatic trypsin inhibitor (BPTI). While conkunitzin-S1 and alpha-dendrotoxin are 42% identical in amino-acid sequence, conkunitzin-S1 has only four of the six cysteines normally found in Kunitz proteins. Here, the crystal structure of conkunitzin-S1 is reported. Conkunitzin-S1 adopts the canonical 3(10)-beta-beta-alpha Kunitz fold complete with additional distinguishing structural features including two completely buried water molecules. The crystal structure, although completely consistent with previously reported NMR distance restraints, provides a greater degree of precision for atomic coordinates, especially for S atoms and buried solvent molecules. The region normally cross-linked by cysteines II and IV in other Kunitz proteins retains a network of hydrogen bonds and van der Waals interactions comparable to those found in alpha-dendrotoxin and BPTI. In conkunitzin-S1, glycine occupies the sequence position normally reserved for cysteine II and the special steric properties of glycine allow additional van der Waals contacts with the glutamine residue substituting for cysteine IV. Evolution has thus defrayed the cost of losing a disulfide bond by augmenting and optimizing weaker yet nonetheless effective non-covalent interactions.