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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Insights into the mode of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures.
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Insights into the mode of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures.

机译：从高分辨率晶体结构深入了解抑制人线粒体单胺氧化酶B的模式。

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Monoamine oxidase B (MAO-B) is an outer mitochondrial membrane-bound enzyme that catalyzes the oxidative deamination of arylalkylamine neurotransmitters and has been a target for a number of clinically used drug inhibitors. The 1.7-A structure of the reversible isatin-MAO-B complex has been determined; it forms a basis for the interpretation of the enzyme's structure when bound to either reversible or irreversible inhibitors. 1,4-Diphenyl-2-butene is found to be a reversible MAO-B inhibitor, which occupies both the entrance and substrate cavity space in the enzyme. Comparison of these two structures identifies Ile-199 as a gate either separation or fusion of the two cavities. Inhibition of the enzyme with N-(2-aminoethyl)-p-chlorobenzamide results in the formation of a covalent N(5) flavin adduct with the phenyl ring of the inhibitor occupying a position in the catalytic site overlapping that of isatin. Inhibition of MAO-B with the clinically used trans-2-phenylcyclopropylamine results in the formationof a covalent C(4a) flavin adduct with an opened cyclopropyl ring and the phenyl ring in a parallel orientation to the flavin. The peptide bond between the flavin-substituted Cys-397 and Tyr-398 is in a cis conformation, which allows the proper orientation of the phenolic ring of Tyr-398 in the active site. The flavin ring exists in a twisted nonplanar conformation, which is observed in the oxidized form as well as in both the N(5) and the C(4a) adducts. An immobile water molecule is H-bonded to Lys-296 and to the N(5) of the flavin as observed in other flavin-dependent amine oxidases. The active site cavities are highly apolar; however, hydrophilic areas exist near the flavin and direct the amine moiety of the substrate for binding and catalysis. Small conformational changes are observed on comparison of the different inhibitor-enzyme complexes. Future MAO-B drug design will need to consider "induced fit" contributions as an element in ligand-enzyme interactions.
机译：单胺氧化酶B（MAO-B）是线粒体外膜结合酶，可催化芳基烷基胺神经递质的氧化脱氨作用，并且已成为许多临床使用的药物抑制剂的目标。已确定可逆的isatin-MAO-B复合物的1.7-A结构；当与可逆或不可逆抑制剂结合时，它成为解释酶结构的基础。发现1,4-二苯基-2-丁烯是一种可逆的MAO-B抑制剂，它同时占据了酶的入口和底物腔空间。两种结构的比较将Ile-199识别为两个腔体分离或融合的门。用N-（2-氨基乙基）-对氯苯甲酰胺抑制该酶导致形成共价N（5）黄素加合物，而该抑制剂的苯环占据催化位点上与伊斯丁素重叠的位置。临床上使用的反式-2-苯基环丙胺对MAO-B的抑制作用导致形成了一个共价的C（4a）黄素加合物，该化合物的开环丙基环和苯环均与黄素平行。黄素取代的Cys-397和Tyr-398之间的肽键呈顺式构象，可在活性位点正确定位Tyr-398的酚环。黄素环以扭曲的非平面构象存在，以氧化形式以及在N（5）和C（4a）加合物中均可见到。如在其他黄素依赖性胺氧化酶中所观察到的，固定的水分子与Lys-296和黄素的N（5）H键合。活性部位的空腔高度非极性。然而，亲水性区域存在于黄素附近，并引导底物的胺部分进行结合和催化。比较不同的抑制剂-酶复合物时，观察到小的构象变化。未来的MAO-B药物设计将需要考虑“诱导适合”作用作为配体-酶相互作用的一个元素。

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