Dialing down caspase-7 through allosteric control: An integrated approach
通过变构控制降低 caspase-7:一种综合方法
基本信息
- 批准号:10259744
- 负责人:
- 金额:$ 30.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-15 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAcylationAffectApoptosisApoptoticBindingBiophysicsCASP7 geneCaspaseCellsChargeChemicalsCleaved cellComplexCrystallizationDataDepositionDevelopmentDiseaseDrug TargetingEnzyme PrecursorsEnzymesFamilyFoundationsGoalsHumanHydrolysisInflammationInflammatoryKineticsKnowledgeLearningLigationMalignant NeoplasmsMeasurableMethodsModelingMolecular ConformationNerve DegenerationPathway interactionsPeptide HydrolasesPeptidesPharmaceutical PreparationsPharmacologic SubstancePositioning AttributePost-Translational Protein ProcessingProcessPropertyResolutionRoleSchemeSeriesSourceSpecificityStimulusStructural ModelsStructureStructure-Activity RelationshipSurface Plasmon ResonanceSystemTestingWorkX-Ray Crystallographybasebiophysical techniquescheminformaticsdeacylationdrug discoveryflexibilitygenetic regulatory proteininhibitor/antagonistinsightinterestmolecular dynamicsnovelresponsescreeningsimulationsmall molecule
项目摘要
Our goal is to provide a physical and chemical rationale for how human caspase-7 (C7) is allosterically
controlled, particularly by small molecules. Caspase dysregulation, both catalytic and autocatalytic,
has been implicated in numerous neurodegenerative, inflammatory diseases and cancers. Due to a
highly charged active site, with low druggability and selectivity problems, development of active site
inhibitors has been problematic. However, there has been enormous interest in targeting an allosteric
pocket of C7, which is located more than 17 Å from the active site. The current proposal includes data
that represents a breakthrough advance in our understanding of how small drug-like molecules may
be used to allosterically “dial down” the activity of C7. This initial groundwork has been made possible
by advances in Fragment Based Drug Discovery (FBDD), which includes a confluence of chemical
informatics, biophysical methods such as Surface Plasmon Resonance, X-ray crystallography and
molecular dynamics. The work described in this proposal centers on our discovery of a series of
reversible allosteric inhibitors that bind in this allosteric pocket, which are the first drug-like compounds
to show such activity in caspases. The allosteric effectors obtained from our FBDD campaign were
used to elucidate several high resolution crystal structures of the inhibited complex, which revealed a
way forward for specific allosteric control for this enzyme. The use of FBDD, as illustrated by our two
inhibited high resolution crystal structures, PDB-ID 5V6U and 5V6Z, provide us with the first rational
basis for structure-activity relationships for reversible allosteric inhibitors for the executioner caspase
class of drug targets. These two structures clearly show that binding of the allosteric inhibitor to the
remote allosteric pocket of C7, yields structures with C7’s catalytic thiolate (Cys186) oriented in a non-
productive conformation (pointing into the P1 pocket instead of into the active site). Another important
feature of these allosterically inhibited complexes is a large increase in crystallographic B-factors
(relative to crystal structures of uninhibited C7) of a number of important loop regions. This proposal
will focus on obtaining high resolution structures of the many other distinct allosteric effectors resulting
from our FBDD campaign, which have not been co-crystallized with C7, including 13 confirmed
inhibitors, 5 binders that do not inhibit, and one activator; completion of this work will provide a
structural Rosetta Stone (an ability to directly compare inhibitor, non-inhibitor and activator) for
understanding how C7’s catalytic power is affected by remote ligation at the allosteric pocket. Upon
successful completion, not only will we learn what chemical space occupancy in the C7 allosteric
pocket results in inhibition, but more importantly, we will know how these remotely bound species are
achieving their dampening of C7’s catalytic power.
我们的目标是为人类 caspase-7 (C7) 的变构提供物理和化学原理
控制,特别是由小分子控制。 Caspase 失调,催化和自催化,
与许多神经退行性疾病、炎症性疾病和癌症有关。由于一个
高电荷活性位点,具有低成药性和选择性问题,活性位点的开发
抑制剂一直是个问题。然而,人们对靶向变构
C7 的口袋,距离活性位点超过 17 Å。当前提案包含数据
这代表着我们对药物样小分子如何发挥作用的理解取得了突破性进展
用于变构“降低”C7 的活性。初步的基础工作已经成为可能
基于片段的药物发现 (FBDD) 的进步,其中包括化学物质的融合
信息学、生物物理方法,如表面等离子共振、X 射线晶体学和
分子动力学。本提案中描述的工作集中于我们发现的一系列
结合在这个变构袋中的可逆变构抑制剂,这是第一个类药物化合物
在半胱天冬酶中显示这种活性。从我们的 FBDD 活动中获得的变构效应器是
用于阐明受抑制复合物的几种高分辨率晶体结构,揭示了
该酶的特异性变构控制的前进方向。 FBDD 的使用,如我们两个所示
抑制高分辨率晶体结构 PDB-ID 5V6U 和 5V6Z 为我们提供了第一个理性的
刽子手半胱天冬酶可逆变构抑制剂的结构-活性关系的基础
药物靶标的类别。这两个结构清楚地表明变构抑制剂与
C7 的远程变构口袋,产生具有 C7 催化硫醇盐 (Cys186) 取向的结构
生产性构象(指向 P1 口袋而不是活性位点)。另一个重要的
这些变构抑制复合物的特点是晶体 B 因子大幅增加
(相对于不受抑制的 C7 的晶体结构)许多重要的环区域。这个提议
将重点关注获得许多其他不同变构效应子的高分辨率结构
来自我们的 FBDD 活动,尚未与 C7 共同结晶,其中包括 13 个已确认的活动
抑制剂、5 种不抑制的结合剂和 1 种激活剂;这项工作的完成将提供
结构罗塞塔石碑(直接比较抑制剂、非抑制剂和激活剂的能力)
了解变构袋处的远程连接如何影响 C7 的催化能力。之上
成功完成,我们不仅将了解 C7 变构中的化学空间占用情况
口袋会导致抑制,但更重要的是,我们将知道这些远程结合的物种是如何
从而抑制 C7 的催化能力。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Michael Ashley Spies其他文献
Michael Ashley Spies的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Michael Ashley Spies', 18)}}的其他基金
Dialing down caspase-7 through allosteric control: An integrated approach
通过变构控制降低 caspase-7:一种综合方法
- 批准号:
10027338 - 财政年份:2020
- 资助金额:
$ 30.9万 - 项目类别:
Dialing down caspase-7 through allosteric control: An integrated approach
通过变构控制降低 caspase-7:一种综合方法
- 批准号:
10649449 - 财政年份:2020
- 资助金额:
$ 30.9万 - 项目类别:
Dialing down caspase-7 through allosteric control: An integrated approach
通过变构控制降低 caspase-7:一种综合方法
- 批准号:
10439889 - 财政年份:2020
- 资助金额:
$ 30.9万 - 项目类别:
Exploiting Enzyme Plasticity in Drug Discovery: application to glutamate racemase
在药物发现中利用酶可塑性:在谷氨酸消旋酶中的应用
- 批准号:
9134161 - 财政年份:2012
- 资助金额:
$ 30.9万 - 项目类别:
Exploiting Enzyme Plasticity in Drug Discovery: application to glutamate racemase
在药物发现中利用酶可塑性:在谷氨酸消旋酶中的应用
- 批准号:
8534789 - 财政年份:2012
- 资助金额:
$ 30.9万 - 项目类别:
Exploiting Enzyme Plasticity in Drug Discovery: application to glutamate racemase
在药物发现中利用酶可塑性:在谷氨酸消旋酶中的应用
- 批准号:
8730183 - 财政年份:2012
- 资助金额:
$ 30.9万 - 项目类别:
Exploiting Enzyme Plasticity in Drug Discovery: application to glutamate racemase
在药物发现中利用酶可塑性:在谷氨酸消旋酶中的应用
- 批准号:
8238516 - 财政年份:2012
- 资助金额:
$ 30.9万 - 项目类别:
Exploiting Enzyme Plasticity in Drug Discovery: application to glutamate racemase
在药物发现中利用酶可塑性:在谷氨酸消旋酶中的应用
- 批准号:
9381976 - 财政年份:2012
- 资助金额:
$ 30.9万 - 项目类别:
Determination of the Biological Roles and Chemical Mechanisms of the Glutamate Ra
谷氨酸 Ra 的生物学作用和化学机制的测定
- 批准号:
7882479 - 财政年份:2009
- 资助金额:
$ 30.9万 - 项目类别:
Determination of the Biological Roles and Chemical Mechanisms of the Glutamate Ra
谷氨酸 Ra 的生物学作用和化学机制的测定
- 批准号:
7740323 - 财政年份:2009
- 资助金额:
$ 30.9万 - 项目类别:
相似海外基金
Greasing endocytosis in plants - understanding the role of S-acylation in receptor kinase function and internalisation
植物中的润滑内吞作用 - 了解 S-酰化在受体激酶功能和内化中的作用
- 批准号:
BB/Y003756/1 - 财政年份:2024
- 资助金额:
$ 30.9万 - 项目类别:
Research Grant
Ghrelin de-acylation inhibitors as novel compounds for Parkinson's dementia
生长素释放肽去酰化抑制剂作为治疗帕金森痴呆症的新型化合物
- 批准号:
MR/Y503435/1 - 财政年份:2024
- 资助金额:
$ 30.9万 - 项目类别:
Research Grant
S-acylation-dependent regulation of cytokine receptor signaling and cardiac maladaptation
细胞因子受体信号传导和心脏适应不良的 S-酰化依赖性调节
- 批准号:
10561406 - 财政年份:2023
- 资助金额:
$ 30.9万 - 项目类别:
Comprehensive analysis of acidic patch binder using histone acylation catalysts
使用组蛋白酰化催化剂综合分析酸性贴片粘合剂
- 批准号:
22KJ1113 - 财政年份:2023
- 资助金额:
$ 30.9万 - 项目类别:
Grant-in-Aid for JSPS Fellows
S-Acylation of transmembrane proteins in the early secretory pathway
早期分泌途径中跨膜蛋白的 S-酰化
- 批准号:
BB/X001504/1 - 财政年份:2023
- 资助金额:
$ 30.9万 - 项目类别:
Research Grant
N-terminal acylation and sorting of Helicobacter pylori lipoproteins and their role in host response to infection
幽门螺杆菌脂蛋白的 N 末端酰化和分选及其在宿主感染反应中的作用
- 批准号:
10584620 - 财政年份:2022
- 资助金额:
$ 30.9万 - 项目类别:
The Molecular Mechanisms of Glycolytic Enzyme S-acylation in Neurons
神经元糖酵解酶S-酰化的分子机制
- 批准号:
576016-2022 - 财政年份:2022
- 资助金额:
$ 30.9万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Master's
Anti-CRISPR-mediated Acylation and Bioreversible Esterification for Precision Genome Editing
用于精准基因组编辑的抗 CRISPR 介导的酰化和生物可逆酯化
- 批准号:
10657417 - 财政年份:2022
- 资助金额:
$ 30.9万 - 项目类别:
High Throughput Screen for Inhibitors of the YEATS2 Histone Acylation Reader
YEATS2 组蛋白酰化酶抑制剂的高通量筛选
- 批准号:
10389517 - 财政年份:2022
- 资助金额:
$ 30.9万 - 项目类别:
Roles of KAT8 complexes in governing histone acylation and mouse cerebral development
KAT8复合物在控制组蛋白酰化和小鼠大脑发育中的作用
- 批准号:
RGPIN-2019-07122 - 财政年份:2022
- 资助金额:
$ 30.9万 - 项目类别:
Discovery Grants Program - Individual