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相关概念视频

Conjugated Proteins02:50

Conjugated Proteins

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Simple proteins and protein complexes contain only amino acids. In contrast, many other proteins, called conjugated proteins, covalently bond with non-protein moieties.
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The pentose sugar in DNA is deoxyribose, while in RNA the pentose sugar is ribose. The difference between the sugars is the presence of the hydroxyl group on the ribose's second carbon and a hydrogen on the deoxyribose's second carbon. The phosphate residue attaches to the hydroxyl group of the 5′ carbon of one sugar and the hydroxyl group of the 3′ carbon of the sugar of the next nucleotide, which forms  a 5′ to 3′ phosphodiester linkage.
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During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA.  Marilyn Kozak discovered that the sequence RCCAUGG (where R...
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Viruses are extraordinarily diverse in shape and size, but they all have several structural features in common. All viruses have a core that contains a DNA- or RNA-based genome. The core is surrounded by a protective coat of proteins called the capsid. The capsid is composed of subunits called capsomeres. The capsid and genome-containing core are together known as the nucleocapsid.
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Proteins can form homomeric complexes with another unit of the same protein or heteromeric complexes with different types.  Most protein complexes self-assemble spontaneously via ordered pathways, while some proteins need assembly factors that guide their proper assembly. Despite the crowded intracellular environment, proteins usually interact with their correct partners and form functional complexes.
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Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
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小分子与SARS-CoV-2 nsp10-nsp14 ExoN复合体结合的结构基础

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概括

研究人员通过研究SARS-CoV-2 (严重急性呼吸系统综合征冠状病毒-2) nsp10-nsp14复合体,确定了新的药物标. 碎片查揭示了新的结合部位,为开发抗病毒药物提供了起点.

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科学领域:

  • 病毒学 病毒学
  • 结构生物学 结构生物学
  • 药物发现 药物发现 药物发现

背景情况:

  • 严重急性呼吸系统综合征冠状病毒-2 (SARS-CoV-2) 导致全球大流行.
  • SARS-CoV-2 的非结构蛋白 10 (nsp10) 和 14 (nsp14) 对于病毒复制至关重要,是潜在的药物标.
  • 由nsp10刺激的NSP14的3'-to-5'外核酶 (ExoN) 活性,通过纠正RNA合成中的错误,赋予了对核类型药物的耐药性.

研究的目的:

  • 阐明nsp10-nsp14复合体功能的结构基础,并确定新的抑制策略.
  • 为了描述nsp10-nsp14 ExoN复合体内的构造变化.
  • 为开发针对SARS-CoV-2 nsp10-nsp14相互作用的药物发现基于碎片的新起点.

主要方法:

  • 结晶 nsp10-nsp14 ExoN 复合物,使其能够进行结构分析.
  • 进行X射线片段查,以确定该复合体上的新型结合点.
  • 微尺度热泳以估计已识别的碎片的结合亲缘关系.
  • 调查已识别的网站,以潜在抑制nsp10-nsp14蛋白质-蛋白质相互作用.

主要成果:

  • 结晶了nsp10-nsp14 ExoN复合物,揭示了不同的构造,并将像His268这样的关键残留物陷入了不同的方向.
  • 在nsp10-nsp14接口,链区域和nsp10.上确定了五个新的碎片结合点.
  • 一个接口部位显示了九个相关片段的集群,使最初的结构-活性关系研究成为可能,并且对不同部位有选择性结合的反体.

结论:

  • 已识别的碎片代表了针对SARS-CoV-2的基于结构的药物设计的新起点.
  • 发现的结合位提供了开发抑制剂的机会,这些抑制剂会破坏nsp10-nsp14蛋白质-蛋白质相互作用.
  • 了解形态动态和碎片结合,为开发有效的抗病毒疗法提供了基础.