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首页> 外文学位 >Ligand binding in human inosine 5'-monophosphate dehydrogenase type I and type II: Crystallographic and kinetic studies.
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Ligand binding in human inosine 5'-monophosphate dehydrogenase type I and type II: Crystallographic and kinetic studies.

机译：I型和II型人肌苷5'-单磷酸脱氢酶中的配体结合：晶体学和动力学研究。

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摘要

IMPDH catalyzes the NAD-dependent oxidation of inosine 5′ -monophosphate (IMP) to xanthosine 5′-monophosphate. Effective drugs against this attractive anti-cancer target would specifically inhibit the inducible type II isoform, while leaving the type I isoform unaffected for ‘housekeeping’ production of guanine nucleotides. This study reports binding interactions between four ligands and the human enzymes inosine 5′-monophosphate dehydrogenase (IMPDH) type I and type II characterized by X-ray crystallography and enzyme kinetic studies.; The crystal structure of the type II isoform with the first crystallographically observed bound NAD is presented in Chapter 2. This structure reveals important interactions between the NAD carboxamide group and active site residues and further demonstrates the flexibility of the active-site loop in accommodating non-native ligands.; The first crystal structure of human IMPDH type I is reported in Chapter 3. This structure confirms the general structural similarity between the two isoforms in the active site region. This similarity is an important prerequisite for any drug design program with type II-specificity as a goal.; Mycophenolic Acid (MPA) is a successful immunosuppressive agent but is ineffective as an anticancer agent. C2-MAD is a hybrid compound with the ‘head’ of MPA attached to the adenosine ‘tail’ portion of NAD in an attempt to improve on the bioavailability of MPA. The crystal structure of IMPDH type II with C2-MAD bound is presented in Chapter 4. This structure shows that the MPA ‘head’ of C2-MAD binds much like MPA while the adenosine ‘tail’ interacts much like an NAD analog previously studied, revealing that the two subsites can be coupled in a single inhibitor. Further, the C2-MAD and NAD-bound structures reveal that dinucleotide binding only partially orders the active site ‘flap’. The existing hypothesis that dinucleotide binding orders the flap therefore needs to be revised in light of these findings. The first available enzyme-bound conformation of ribavirin monophosphate, an important immunosuppressive agent, is also described in Chapter 4, and a putative ion-binding site is identified.; Appendix A describes the kinetic results of a set of novel compounds that are modifications of MPA and are the result of several rounds of structure-aided drug design.
机译：IMPDH催化肌苷5 '-单磷酸盐的NAD依赖性氧化反应，生成肌苷5 '-单磷酸盐。针对这种有吸引力的抗癌靶标的有效药物将特异性抑制可诱导的II型同工型，而I型同工型不会受到鸟嘌呤核苷酸“管家”生产的影响。该研究报道了通过X射线晶体学和酶动力学研究表征的四个配体与人I型和II型肌苷5 '单磷酸脱氢酶（IMPDH）之间的结合相互作用。第2章介绍了具有第一个晶体学上观察到的结合NAD的II型同工型的晶体结构。该结构揭示了NAD羧酰胺基团与活性位点残基之间的重要相互作用，并进一步证明了活性位点环在适应非NAD时的灵活性。天然配体。人类IMPDH I型的第一个晶体结构在第3章中报道。该结构证实了活性位点区域中两个同工型之间的一般结构相似性。这种相似性是任何以II型特异性为目标的药物设计计划的重要前提。麦考酚酸（MPA）是一种成功的免疫抑制剂，但不能有效用作抗癌剂。 C2-MAD是一种杂化化合物，其MPA的“头部”附着在NAD的腺苷“尾部”部分，旨在改善MPA的生物利用度。在第4章中介绍了具有C2-MAD结合的II型IMPDH的晶体结构。该结构表明，C2-MAD的MPA“头部”与MPA的结合非常相似，而腺苷“尾巴”的相互作用与之前研究的NAD类似物非常相似，揭示两个亚位点可以在单个抑制剂中偶联。此外，C2-MAD和NAD结合的结构表明，二核苷酸结合仅部分地将活性位点“襟翼”排序。因此，根据这些发现，需要修正二核苷酸结合使皮瓣排列的假设。利巴韦林单磷酸酯（一种重要的免疫抑制剂）的第一个可用的酶结合构象也在第4章中进行了描述，并确定了一个假定的离子结合位点。附录A描述了一系列新颖化合物的动力学结果，这些化合物是MPA的修饰，是几轮结构辅助药物设计的结果。

著录项

  • 作者

    Risal, Dipesh.;

  • 作者单位

    The University of Rochester.;

  • 授予单位 The University of Rochester.;
  • 学科 Biophysics General.; Biology Molecular.; Chemistry Pharmaceutical.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 146 p.
  • 总页数 146
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物物理学;分子遗传学;药物化学;
  • 关键词

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