结核菌 (Mycobacterium tuberculosis) 的结构和抑制机制 重要输送物流流蛋白A
Nitesh Kumar Khandelwal1, Meghna Gupta1,2, James E Gomez3
1Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94143, USA.
bioRxiv : the preprint server for biology
|September 16, 2024
概括
两种新型化合物抑制了Mycobacterium tuberculosis (Mtb) 中必需的排泄EfpA,为结核病治疗提供了新的策略. 它们独特的结合机制揭示了协同药物组合的潜力.
科学领域:
- 结构生物学 结构生物学
- 药物发现 药物发现 药物发现
- 微生物学 微生物学
背景情况:
- 结核菌菌 (Mtb) 需要必要的排泄,以求生存和耐药性.
- 鉴定这些的新型抑制剂对于开发新的抗结核疗法至关重要.
研究的目的:
- 为了识别和表征MTB流量EfpA的基本抑制剂.
- 阐明新型化合物BRD-8000.3和BRD-9327.3抑制的结构机制.
- 探索这些抑制剂在结核病联合治疗中的潜力.
主要方法:
- 在Mtb.进行化学遗传学查.
- 使用冷电子显微镜 (2.7 - 3.4 Å分辨率) 确定具有结合抑制剂的EfpA结构.
主要成果:
- 两种化合物,BRD-8000.3和BRD-9327,被确定为EfpA抑制剂.
- BRD-8000.3 阻断了脂质接入路径,可能会抑制脂质运输.
- BRD-9327通过干扰基质转移所需的传送器动态运动来抑制EfpA.
- 这些独特的机制解释了观察到的协同效应,并表明EfpA在脂质运输中的作用.
结论:
- 已识别的抑制剂通过不同的机制与EfpA结合,为它们的协同活性提供结构基础.
- 这些发现支持开发针对EfpA的结核病组合疗法.
- 这项研究表明EfpA作为脂质载体的潜在作用,为治疗干预开辟了新的途径.
相关概念视频
ABC Transporters: Importer
2.7K
ATP-binding cassette or ABC transporters are a class of ATP-driven pumps that hydrolyze ATP to move solutes across the membrane. They can be grouped into importers and exporters. While exporters are present in all domains of life, importers exist only in bacteria and some plants.
In bacteria, based on the number of transmembrane helices and the chemical nature of their substrates, the ABC importers can be divided into three types:
In bacteria, based on the number of transmembrane helices and the chemical nature of their substrates, the ABC importers can be divided into three types:
2.7K
ABC Transporters: Exporter
4.2K
ATP-binding cassette or ABC transporter is the largest superfamily of integral membrane proteins. The transporters have transmembrane-binding domains (TMDs) and nucleotide-binding domains (NBDs). The TMDs are specific to their substrates, whereas the NBDs are similar to engines that complete ATP hydrolysis to complete the substrate transport. They can be full transporters consisting of two TMDs and NBDs, half transporters with one TMD and NBD, while some encoded with a single TMD or NBD are...
4.2K
Carrier-Mediated Transport
313
Carrier-mediated transport is a pivotal process in drug absorption, particularly for lipid-insoluble drugs, and encompasses facilitated diffusion and active transport. Facilitated diffusion allows drugs to move along their concentration gradient without energy expenditure, while active transport utilizes ATP to drive drug movement against this gradient.
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
313
Drug Elimination by Renal Route: Tubular Secretion
2.3K
Once the process of glomerular filtration is completed, blood carrying unfiltered drug molecules traverses through efferent arterioles and makes its way into the peritubular capillaries in the proximal tubule. A variety of carriers play a pivotal role in actively secreting drugs from these peritubular capillaries into the tubular fluid. The organic anion transporter transfers acidic drugs, against an electrochemical gradient, from the peritubular capillaries into the renal tubule cells and...
2.3K
The Electron Transport Chain
16.3K
The electron transport chain or oxidative phosphorylation is an exothermic process in which free energy released during electron transfer reactions is coupled to ATP synthesis. This process is a significant source of energy in aerobic cells, and therefore inhibitors of the electron transport chain can be detrimental to the cell's metabolic processes.
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q...
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q...
16.3K
The Significance of Membrane Transport
24.2K
The transport of solutes across the cell membrane is essential for metabolic processes, like maintaining cell size and volume, generating the action potential, exchanging nutrients and gases, etc. Membrane transport can be either passive or active. It can be simple diffusion, facilitated, or mediated transport aided by transport proteins such as transporters and channels.
Transporters facilitate either an active or passive movement of solutes. They can allow a single-molecule transport down its...
Transporters facilitate either an active or passive movement of solutes. They can allow a single-molecule transport down its...
24.2K


