The global regulation of dynamics and structure mediated by single hydride in a family of reductases
还原酶家族中单个氢化物介导的动力学和结构的全局调节
基本信息
- 批准号:10296136
- 负责人:
- 金额:$ 30.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-15 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:Active SitesAddressAffinityAmidesBilirubinBiliverdin reductaseBiliverdineBindingBiochemicalBiologicalCellsChemicalsCoenzyme ACoenzymesCommunicationCoupledCouplingCulicidaeDataDistalEnzymesEnzymes and CoenzymesFamilyFamily memberFlavinsGlobal ChangeHematopoieticHumanLinkMapsMediatingMethodsMolecular ConformationMonitorMutateMutationNADPNatureOrganismOxidation-ReductionOxidesOxidoreductasePlant RootsProtein EngineeringProteinsPublicationsRegulationRelaxationResolutionRoentgen RaysRoleSiteStructureSystemX-Ray Crystallographybasebiophysical techniquesenzyme structurehuman pathogeninnovationinsightmemberoxidationstereochemistrytherapeutic targettumor
项目摘要
PROJECT SUMMARY
We have discovered that a single hydride induces global changes to both structure and dynamics within
multiple members of an enzyme family, providing a fundamental link between enzyme structure, dynamics, and
allostery that has implications to the entire oxidoreductase superfamily. Specifically, the BLVRB family are
NADPH-dependent reductases present in multiple organisms where they regulate cellular redox through the
reduction of biliverdin-to-bilirubin and a wide array of flavin substrates. While our recent publications have
revealed that coenzyme binding is coupled to global conformational and dynamic changes, we have now
discovered that there are largescale changes coupled to the oxidation state of the coenzyme as far as 23 Å
away. Thus,
structural
catalytic
the central premise of this application is that a coenzyme's hydride is globally coupled to both
and dynamic changes within an enzyme family and that such global coupling is integrally related to
function.
The novelty here is that we will explicitly determine how a single hydride, i.e., the difference between
NADPH/NADP+, is globally linked (Aim 1) and how this global coupling controls enzyme function (Aim 2).
Further innovation includes the following. First, we have discovered that hydride-coupled networks can be
modulated by mutations directly to the enzyme/coenzyme interface but also to distally coupled sites, which
gives us the unique opportunity to determine the role of these networks in function. Second, we have
discovered that evolutionarily changing residues modulate hydride coupled networks and function, providing
remarkable insight into the evolutionary role of hydride-mediated coupling and function. Evolutionary
differences will therefore be exploited to identify allosteric networks coupled to the oxidative state of the
coenzyme and simultaneously reveal their evolutionary roles in function. Based on our preliminary data that
includes NMR, X-ray crystallographic, and biochemical studies, we hypothesize that the coenzyme oxidation
induces its own conformational change that is further propagated globally through the enzyme in multiple
BLVRB family members (referred to as “insideout” coupling) and that networks coupled to these changes
modulate function (referred to as “outsidein” coupling). We will address this hypothesis through the following:
Aim 1) Determine how a single hydride modulates the global dynamics and structure within the BLVRB
family of enzymes. NMR solution studies using CSPs, relaxation studies, and ensembles methods will be
used to determine how a single hydride imparts its global regulation to dynamics and structure using three
distinct BLVRB family members with both active site and distal differences (human, hyrax, and mosquito).
Aim 2) Determine the functional role of networks coupled to the oxidative state of the coenzyme.
Biochemical and biophysical methods will be used to determine the functional role of hydride-mediated global
regulation, which include both the role of direct interactions with the coenzyme's hydride as well as the role of
networks of communication coupled to the coenzyme (allostery).
项目总结
项目成果
期刊论文数量(0)
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