FK506 结合蛋白 FKBP12 构象不稳定性的传播

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS ACS Applied Bio Materials Pub Date : 2023-12-23 DOI:10.1016/j.bbapap.2023.140990
David M. LeMaster, Qamar Bashir, Griselda Hernández
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引用次数: 0

摘要

FKBP12 是 FK506 结合结构域的原型,它定义了 FKBP 蛋白家族,该家族参与调节各种不同的生理信号转导过程。由于药物 FK506 和雷帕霉素能抑制许多 FKBP 蛋白,因此有必要开发在该家族中具有选择性的疗法。众所周知,FKBP 结构域的β4-β5 长环可调节类固醇激素受体的转录活性,并似乎参与调节心脏和骨骼肌雷诺丁受体的钙通道活性。FKBP12 的 β4-β5 环已被证明发生了广泛的构象动态变化,我们在此报告了该环中一系列突变变体的氢交换测量结果,结果表明这些动态变化偏离了双态动力学。除了先前表征的该环尖端附近的局部转变外,我们还提出了该环茎中第二个构象动态位点的证据。这些依赖于突变的氢交换效应延伸到了β4-β5 环之外,主要是通过破坏 Gly 58 氨基酸和 Tyr 80 羰基氧之间的氢键来实现的。突变诱导的 Gly 58 和 Tyr 80 之间裂隙的打开不仅调节了蛋白质的整体稳定性,还促进了远处 β2-β3a 发夹的构象转变,从而调节了先前为利用同源位点的局部构象转变而设计的 FKBP51 选择性抑制剂的结合亲和力。
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Propagation of conformational instability in FK506-binding protein FKBP12

FKBP12 is the archetype of the FK506 binding domains that define the family of FKBP proteins which participate in the regulation of various distinct physiological signaling processes. As the drugs FK506 and rapamycin inhibit many of these FKBP proteins, there is need to develop therapeutics which exhibit selectivity within this family. The long β45 loop of the FKBP domain is known to regulate transcriptional activity for the steroid hormone receptors and appears to participate in regulating calcium channel activity for the cardiac and skeletal muscle ryanodine receptors. The β45 loop of FKBP12 has been shown to undergo extensive conformational dynamics, and here we report hydrogen exchange measurements for a series of mutational variants in that loop which indicate deviations from a two-state kinetics for those dynamics. In addition to a previously characterized local transition near the tip of this loop, evidence is presented for a second site of conformational dynamics in the stem of this loop. These mutation-dependent hydrogen exchange effects extend beyond the β45 loop, primarily by disrupting the hydrogen bond between the Gly 58 amide and the Tyr 80 carbonyl oxygen which links the two halves of the structural rim that surrounds the active site cleft. Mutationally-induced opening of the cleft between Gly 58 and Tyr 80 not only modulates the global stability of the protein, it promotes a conformational transition in the distant β23a hairpin that modulates the binding affinity for a FKBP51-selective inhibitor previously designed to exploit a localized conformational transition at the homologous site.

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来源期刊
ACS Applied Bio Materials
ACS Applied Bio Materials Chemistry-Chemistry (all)
CiteScore
9.40
自引率
2.10%
发文量
464
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