STRUCTURE OF TOXOPLASMA GONDII ADENOSINE KINASE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 腺苷激酶（Adenosine kinase，AK）是寄生虫嘌呤代谢的关键酶，也是弓形虫感染治疗的潜在靶点。 未配体AK和AK与腺苷（或7-碘杀结核菌素）和不可水解的ATP类似物AMP-PCP复合的初始结构揭示了一种新的催化机制。 腺苷结合后GG开关触发的结构域闭合将ATP的腺苷和<$-磷酸与溶剂隔离。由ATP结合诱导的阴离子空穴的形成完成了催化的结构要求。 后来发表的AK与AMP-PCP复合物的结构（分辨率为1.1）提供了直接证据，证明在mM浓度下ATP结合不需要腺苷结合作为先决条件。 这种二元复合物的整体结构类似于具有开放构象的脱辅基酶。AMP-PCP以两种松弛构象结合，并且不通过Arg 136锚定。 诱导的阴离子空穴与AK/腺苷/AMP-PCP三元复合物中的阴离子空穴相同。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Adenosine kinase (AK) is a key enzyme in purine metabolism in parasites, and a potential chemotherapeutic target for the treatment of Toxoplasma gondii infections. The initial structures of unliganded AK and AK in complex with adenosine (or 7-iodotubercidin) and the non-hydrolysable ATP analog AMP-PCP revealed a novel catalytic mechanism. A domain closure triggered by a GG switch upon adenosine binding sequesters the adenosine and ¿-phosphate of ATP from the solvent. The formation of the anion hole induced by the ATP binding completes the structural requirements for catalysis. A later published structure, which was determined to 1.1 ¿ resolution, of AK complexed with AMP-PCP provided direct evidence that ATP binding at mM concentrations does not require adenosine binding as a prerequisite. The overall structure of this binary complex is similar to the apoenzyme with an open conformation. AMP-PCP is bound in two relaxed conformations and without anchoring by Arg136. The induced anion hole is the same as that in the ternary complex of AK/adenosine/AMP-PCP.