Molecular mechanisms of proteins and complexes involved in signaling, microbial pathogenic processes, and rare diseases

Study of microbial signaling systems as potential targets for antimicrobial interventions. Stablish the molecular basis of signal transduction mechanisms related with two-component and phosphorelay systems studying structures of HKs, hybrid HKs, phosphotransferases and RRs. We will find organic molecules, peptides and recombinant antibodies with potential inhibitory activity to block the catalyzed reactions. .

Understanding molecular mechanisms of Mobile Genetic Elements (MGE) involved in pathogenicity and communication for antimicrobial interventions. Structural characterization of mobilization and communication mechanisms in MGE. Structures of proteins and protein-DNA complexes responsible of: 1) phages and phage-inducible chromosomal islands activation and mobilization between species, 2) communication strategies between MGEs in which the host bacteria also participate. 

Structure, mechanisms, and pathogenic alterations in nucleotide metabolism proteins. We aim to decipher the architecture and functional mechanisms of CAD, the multi-enzymatic complex leading de novo pyrimidine nucleotide synthesis, and human UPRT, a putative uracil phosphoribosyltransferase (UPRT) with a non-enzymatic and yet unknown moonlighting function in nucleotide homeostasis.

Structural basis of translation initiation regulation. Understanding the function of eukaryotic translation initiation factors (eIFs) which lack detailed structural information. Determine domain structures of yeast eIF4A and eIF4B proteins, alone or in complex with each other and with RNA.

Macromolecular complexes involved in eukaryotic gene regulation. Studies on complexes controlling gene regulation, with special focus on complexes involved in cancersuch as ribosome RNA processing and maturation, and ribosome RNA export machinery.

Disease-related proteins of nitrogen metabolism or COVID19-related. Studies on i) pyridoxal phosphate homeostasis protein (PROSC/PLPHP) causing vitamin B6-dependent epilepsy; ii) ornithine transcarbamylase (OTC), focusing on structural analysis of pathogenic variants; iii) carbamoyl phosphate synthetase 1 (CPS1), focusing on conformational intermediates and the active-site tunnel formation; and iv) COVID-19-relevant protein–inhibitor complexes, targeting SARS-CoV-2 spike–ACE2 interactions and their most prevalent variants.

本研究聚焦以微生物信号系统作为抗菌干预潜在靶点的相关课题，旨在阐明与双组分系统及磷酸接力系统相关的信号转导机制的分子基础，通过解析组氨酸激酶（Histidine Kinases, HKs）、杂合组氨酸激酶、磷酸转移酶以及响应调节蛋白（Response Regulators, RRs）的结构，最终筛选具备潜在抑制活性的有机分子、多肽与重组抗体，以阻断其催化反应。

针对参与致病过程与信号交流的移动遗传元件（Mobile Genetic Elements, MGE）的分子机制开展研究，以服务于抗菌干预目标；解析MGE的动员与信号交流机制的结构特征，明确负责以下过程的蛋白质及蛋白质-DNA复合物结构：1）噬菌体与噬菌体诱导性染色体岛的激活及跨物种动员；2）宿主细菌亦参与其中的移动遗传元件间通信策略。

研究核苷酸代谢蛋白的结构、作用机制及致病变异。本研究旨在解析CAD——负责从头合成嘧啶核苷酸的多酶复合体系——的整体架构与功能机制，以及人源尿嘧啶磷酸核糖转移酶（Uracil Phosphoribosyltransferase, UPRT）；该酶为假定的尿嘧啶磷酸核糖转移酶，在核苷酸稳态中具备非酶促且尚未阐明的兼职功能。

解析翻译起始调控的结构基础。针对现有详细结构信息缺失的真核翻译起始因子（eukaryotic translation initiation factors, eIFs）阐明其功能机制，并解析酵母eIF4A与eIF4B蛋白单独状态、彼此结合状态以及与RNA结合状态的结构域结构。

研究真核基因调控相关大分子复合物。聚焦调控基因表达的大分子复合物，重点关注与癌症相关的复合物，如核糖体RNA加工与成熟复合物、核糖体RNA输出机器。

开展氮代谢相关疾病蛋白及新冠病毒（COVID-19）相关蛋白研究，具体包括：i）可引发维生素B6依赖性癫痫的磷酸吡哆醛稳态蛋白（pyridoxal phosphate homeostasis protein, PROSC/PLPHP）；ii）鸟氨酸转氨甲酰酶（Ornithine Transcarbamylase, OTC），重点开展其致病变体的结构分析；iii）氨甲酰磷酸合成酶1（Carbamoyl Phosphate Synthetase 1, CPS1），重点研究其构象中间体与活性位点隧道的形成机制；iv）新冠病毒相关蛋白-抑制剂复合物，针对SARS-CoV-2刺突蛋白与ACE2的相互作用及其主流变体展开研究。