Understanding structural and functional diversity of ATP-PPases using protein domains and functional families in CATH database
Understanding structural and functional diversity of ATP-PPases using protein domains and functional families in CATH database
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DOI：
10.1101/2023.10.12.562014
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发表时间：
2023-10
期刊：
影响因子：
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通讯作者：
V. Waman;Jialin Yin;Neeladri Sen;Mohd Firdaus-Raih;Su Datt Lam;C. Orengo
中科院分区：
文献类型：
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作者：
V. Waman;Jialin Yin;Neeladri Sen;Mohd Firdaus-Raih;Su Datt Lam;C. Orengo
ATP焦磷酸酶（ATP-PPases）是HUP（HIGH-motif proteins，Universal Stress Proteins，ATP-Pyrophosphatase）超家族中最原始的一个分支。有四个不同的ATP-PPase底物特异性组，每个组的成员显示相当大的序列差异，尽管共享相同的催化功能的生活领域。在过去的十年中，ATP-PPase结构域结构的数量增加了20倍以上，最近是由于蛋白质结构预测的进展（例如Alphafold 2）。使用丰富的结构信息，我们已经表征了两个最常见的ATP-PPase底物特异性组，NAD-辅酶A酶（NAD）和GMP辅酶A酶（GMPS）。我们进行了当地的结构和序列之间的NADS和GMPS从不同领域的生活，并确定分类组特定的结构功能基序的比较。由于GMPS和NADS是包括结核分枝杆菌在内的病原微生物的潜在药物靶标，因此细菌GMPS和NADS特异性的结构基序提供了新的见解，可能有助于抗菌药物设计。
ATP-Pyrophosphatases (ATP-PPases) are the most primordial lineage of the large and diverse HUP (HIGH-motif proteins, Universal Stress Proteins, ATP-Pyrophosphatase) superfamily. There are four different ATP-PPase substrate-specificity groups, and members of each group show considerable sequence variation across the domains of life despite sharing the same catalytic function. Over the past decade, there has been a >20-fold expansion in the number of ATP-PPase domain structures most recently from advances in protein structure prediction (e.g. Alphafold2). Using the enriched structural information, we have characterised the two most populated ATP-PPase substrate-specificity groups, the NAD-synthases (NAD) and GMP synthases (GMPS). We performed local structural and sequence comparisons between the NADS and GMPS from different domains of life and identified taxonomic-group specific structural functional motifs. As GMPS and NADS are potential drug targets of pathogenic microorganisms including Mycobacterium tuberculosis, structural motifs specific to bacterial GMPS and NADS provide new insights that may aid antibacterial-drug design.