A Database Of Conserved Domain Alignments

我们正在制作一个专家精选的蛋白质结构域比对数据库，描述蛋白质家族中的序列和3D结构保守，并捕获这些家族中已知的功能多样性。 这些多重序列比对用于生成特定位置的分数矩阵(PSSM)，这些分数矩阵又可用于NCBI的基于网络的蛋白质分类资源。到保守结构域数据库的链接默认来自NCBI？S BLAST资源，http://www.ncbi.nlm.nih.gov/BLAST/，和NCBI？S PubMed/Entrez Browser，http://www.ncbi.nlm.nih.gov/entrez/query.fcgi.中的蛋白质记录欲了解有关CDD和这些搜索服务的更多信息，请访问http://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml.。这些信息服务可用于识别蛋白质序列中的保守结构域。 精选的领域模型总结了家庭成员的已知功能，如果可能的话，使用来自PubMed的相关引用。它们还通过序列和结构比对以及基于证据的相互作用位点特征提供特定于位点的功能注释。CDD比对整理项目不同于以前的努力，它在两个基本方面有所不同：(1)尽可能以定量的方式使用3D结构信息来指导比对，(2)通过共同祖先的血统联系起来的明确的家族和子家族等级，反映每个领域的进化历史。当结构域家族内的3D结构已知时，该信息用于定义保守的3D核心结构，即必须在包括在比对中的所有代表性序列中识别的一组无间隙的块。使用线程或基于结构的比对算法，或者当已知多个结构时，通过结构-结构比对，将代表性序列与该核心结构进行比对。这些步骤可确保较高的对齐精度，以将注释准确传递给通过搜索标识的新族成员。 明确的层次结构确定了每个家族分子进化中的主要基因复制事件。我们的基本策略是使用域序列聚类方法，结合已知的域体系结构和系统发育来识别看起来像是古代正字法组的东西。它们定义了整个“父”对齐的显式注释“子”，进而提供了更具体的功能注释。CDD项目采用高水平的自动化，以产生基于结构的比对，识别候选的正畸分组，用新的序列和结构更新CDD比对，并将结果发布到网络服务器。这些算法和所需的相关软件在另一个项目LM000045-12“保守域数据库的比对工具”中进行了描述。这个项目描述了CDD比对的人类-专家精选。CDD馆长的角色是多方面的。他们首先必须查阅相关的科学文献，对每个领域家族的已知功能进行简明的总结，并选择对NCBI？S网络分类资源用户有用的引文。馆长还必须检查自动序列和结构比较的结果，以推断保守的核心块的位置，这是一个迭代过程，需要关于消除不完整或错误的序列和结构数据的判断。策展人还必须根据可供选择的分子进化和聚类方法的结果的共识，确定明显的正畸类群。到目前为止，策展人小组已经制作了大约1000个经过策划的CDD家族，现在可以通过NCBI的蛋白质分类服务器获得这些家族。

We are producing a database of expert-curated protein domain alignments, describing sequence and 3D-structure conservation within protein families and capturing the known functional diversity within these families. These multiple sequence alignments are used to generate position-specific score matrices (PSSMs), that may in turn be used in NCBI's web-based protein classification resources. Links to the Conserved Domain Database (CDD) are made by default from NCBI?s BLAST resource, http://www.ncbi.nlm.nih.gov/BLAST/, and from protein records in NCBI?s PubMed/Entrez browser, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi. Further information about CDD and these search services is available at http://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml. These information services may be used to identify conserved domains within a protein sequence. Curated domain models summarize the known functions of family members, using relevant citations from PubMed when possible. They also provide site-specific functional annotation, via sequence and structure alignments and via evidence-based interaction-site features. The CDD alignment curation project differs from earlier efforts, upon which it builds, in two fundamental ways: (i) 3D-structure information is used in a quantitative way, whenever possible, to guide alignments, and (ii) an explicit hierarchy of families and subfamilies, related by descent from a common ancestor, reflects the evolutionary history of each domain. When a 3D structure is known within a domain family, this information is used to define a conserved 3D core structure, a set of un-gapped blocks that must be identified in all representative sequences included in the alignment. Representative sequences are aligned to this core structure using threading or structure-based alignment algorithms or, when multiple structures are known, by structure-structure alignment. These procedures assure high alignment accuracy, as needed for accurate transfer of annotation to new family members identified by searching. Explicit hierarchies identify major gene duplication events in the molecular evolution of each family. Our basic strategy is to use domain-sequence clustering methods together with known domain architecture and phylogeny to identify what appear to be ancient orthology groups. These define explicitly annotated "children" of the overall "parent" alignment, and in turn provide more specific functional annotation. The CDD project employs a high level of automation, to produce structure-based alignments, to identify candidate orthology groups, to update CDD alignments with new sequences and structures, and to "publish" the results to web servers. These algorithms and associated software required are described under another project, "Alignment Tools for the Conserved Domain Database," LM000045-12. This project describes human-expert curation of CDD alignments. The role of the CDD curators is multifaceted. They first of all must survey relevant scientific literature, to produce concise summaries of the known functions of each domain family and to choose citations useful to users of NCBI?s web-based classification resources. Curators must also examine the results of automated sequence and structure comparison to infer the location of conserved core blocks, an iterative process that requires judgment with respect to elimination of incomplete or erroneous sequence and structure data. Curators must also identify apparent orthology groups, based on the consensus of results from alternative molecular evolution and clustering methods. The curator group has so far produced about 1000 curated CDD families which are now available via NCBI's protein classification servers.