Three-dimensional structure of human monoamine oxidase A (MAO A): Relation to the structures of rat MAO A and human MAO B
Three-dimensional structure of human monoamine oxidase A (MAO A): Relation to the structures of rat MAO A and human MAO B
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DOI：
10.1073/pnas.0505975102
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发表时间：
2005-09-06
影响因子：
11.1
通讯作者：
Mattevi, A
中科院分区：
文献类型：
--
作者：
De Colibus, L;Li, M;Mattevi, A
描述了重组人单胺氧化酶 A (hMAO A) 作为氯吉林抑制加合物的三维结构。虽然 hMAO A 的链折叠与大鼠 MAO A 和人 MAO B (hMAO 13) 相似，但 hMAO A 的独特之处在于它作为单体结晶，并表现出单体形式的溶液流体动力学行为，而不是 hMAO B 和大鼠 MAO A 的二聚体形式。 hMAO A 的活性位点由约 550 埃 (3) 的单个疏水空腔组成，该空腔比从结构确定的值要小。丙炔苯丙胺抑制 hMAO B（约 700 埃(3)），但大于大鼠 MAO A（约 450 埃(3)）。 hMAO A 活性位点结构的一个重要组成部分是残基 210-216 的环构象，这与 hMAO B 和大鼠 MAO A 的环构象不同。这种结构改变的起源被认为是由酶单体形式的长程相互作用引起的。除了作为开发 hMAO A 特异性抑制剂的基础之外，这些数据还支持 hMAO A 涉及通过 hMAO A 特异性的 Glu-151 -> Lys 突变从二聚体到单体形式的变化 [Andres, A. M., Soldevila, M., Navarro, A., Kidd, K. K., Oliva, B. & Bertranpetit, J. (2004) Hum.热内特. 115、377-386]。这些考虑因素对在人类药物开发中使用非人类来源的 MAO A 提出了质疑。
The three-dimensional structure of recombinant human monoamine oxidase A (hMAO A) as its clorgyline-inhibited adduct is described. Although the chain-fold of hMAO A is similar to that of rat MAO A and human MAO B (hMAO 13), hMAO A is unique in that it crystallizes as a monomer and exhibits the solution hydrodynamic behavior of a monomeric form rather than the dimeric form of hMAO B and rat MAO A. hMAO A's active site consists of a single hydrophobic cavity of approximate to 550 angstrom(3), which is smaller than that determined from the structure of deprenyl-inhibited hMAO B (approximate to 700 angstrom(3)) but larger than that of rat MAO A (approximate to 450 angstrom(3)). An important component of the active site structure of hMAO A is the loop conformation of residues 210-216, which differs from that of hMAO B and rat MAO A. The origin of this structural alteration is suggested to result from long-range interactions in the monomeric form of the enzyme. In addition to serving as a basis for the development of hMAO A specific inhibitors, these data support the proposal that hMAO A involves a change from the dimeric to the monomeric form through a Glu-151 -> Lys mutation that is specific of hMAO A [Andres, A. M., Soldevila, M., Navarro, A., Kidd, K. K., Oliva, B. & Bertranpetit, J. (2004) Hum. Genet. 115, 377-386]. These considerations put into question the use of MAO A from nonhuman sources in drug development for use in humans.