Monday, 18th December 2017

Genome Dynamics and Function

    Structure and Function of Macromolecular Complexes

 

 

Santiago RamonB 400px

 


Santiago Ramón-Maiques

 

ESciStaff

EPublications

 

 

Research summary:

Safeguarding genome integrity is essential for correct cell functioning and to prevent diseases such as cancer. Our group is interested in having a good understanding of central cellular processes affecting the integrity of the genome such as the metabolism of nucleotides, the replication, recombination and repair of DNA, and the maintenance and recognition of chromatin architecture. These tasks are performed by proteins and other macromolecular components that associate forming complex and fascinating cellular machines. We combine protein engineering, X-ray crystallography, single-particle electron microscopy, together with biochemical and functional studies, to understand the structure and function of these macromolecular complexes at the atomic level. This knowledge should guide us in the design of compounds to modulate the activity of these machines, providing new opportunities and strategies for fighting disease.

 

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We study the structure and function of CAD, a multifunctional protein that initiates and controls the de novo biosynthesis of pyrimidine nucleotides. This protein is composed of four enzymatic domains: glutaminase (GLN), carbamoyl phosphate synthetase type II (CPS-II), dihydroorotase (DHO) and aspartate transcarbamoylase (ATC).

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Structures of the DHO and ATC domains of human CAD determined by X-ray crystallography.

       

 

Relevant publications:

  • Moreno-Morcillo M, Grande-García A, Ruiz-Ramos A, Del Caño-Ochoa F, Boskovic J, Ramón-Maiques S. Structural Insight into the Core of CAD, the Multifunctional Protein Leading De Novo Pyrimidine Biosynthesis. Structure. 2017 Jun 6;25(6):912-923.e5. doi: 10.1016/j.str.2017.04.012. Epub 2017 May 25. PubMed PMID: 28552578.
  • Ruiz-Ramos A, Velázquez-Campoy A, Grande-García A, Moreno-Morcillo M, Ramón-Maiques S. Structure and Functional Characterization of Human Aspartate Transcarbamoylase, the Target of the Anti-tumoral Drug PALA. Structure. 2016 Jul 6;24(7):1081-94. doi: 10.1016/j.str.2016.05.001. Epub 2016 Jun 2. PubMed PMID: 27265852.
  • Dramićanin M, López-Méndez B, Boskovic J, Campos-Olivas R, Ramón-Maiques S. The N-terminal domain of MuB protein has striking structural similarity to DNA-binding domains and mediates MuB filament-filament interactions. J Struct Biol. 2015 Aug;191(2):100-11. doi:10.1016/j.jsb.2015.07.004. Epub 2015 Jul 10. PubMed PMID: 26169224.
  • Grande-García A, Lallous N, Díaz-Tejada C, Ramón-Maiques S. Structure, functional characterization, and evolution of the dihydroorotase domain of human CAD. Structure. 2014 Feb 4;22(2):185-98. doi: 10.1016/j.str.2013.10.016. Epub 2013 Dec 12. PubMed PMID: 24332717.
  • Mizuno N, Dramićanin M, Mizuuchi M, Adam J, Wang Y, Han YW, Yang W, Steven AC, Mizuuchi K, Ramón-Maiques S. MuB is an AAA+ ATPase that forms helical filaments to control target selection for DNA transposition. Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):E2441-50. doi: 10.1073/pnas.1309499110. Epub 2013 Jun 17. PubMed PMID: 23776210; PubMed Central PMCID: PMC3703974.