Cristalografía y Biología Estructural = CBE
Some most recent results      (See also our remaining publications & projects)
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Pce, a neumococcal lysine 

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Structure-guided engineering of a receptor-agonist pair for inducible activation of the ABA adaptive response to drought.
Abscisic acid (ABA) is a plant hormone that naturally controls the response of plants in drought situations. Based on the atomic structure of ABA receptor proteins, we have designed a synthetic ABA receptor and a small chemical compound that acting together in plants are capable of activating ABA signaling in plants and very efficiently improving their tolerance to drought.
Science Advances (2023) 9(10)   (doi: 10.1126/sciadv.ade9948)   (see also a short video)


Cyclosporin. Click on it to get a larger image
Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii.
Cyclosporin (CsA) has antiparasite activity against the human pathogen Toxoplasma gondii. In a collaborative effort between University of Verona and the IQFR we characterized the functional and structural properties of two cyclophilins from T. gondii, TgCyp23 and TgCyp18.4. While TgCyp23 is a highly active cis−trans-prolyl isomerase (PPIase) and binds CsA with nanomolar affinity, TgCyp18.4 shows low PPIase activity and is significantly less sensitive to CsA inhibition. The crystal structure of the TgCyp23:CsA complex was solved at 1.1 Å resolution showing the molecular details of CsA recognition by the protein, and revealing relevant differences at the CsA-binding site compared to TgCyp18.4. The biochemical and structural data presented herein represents a relevant step toward understanding the molecular mechanisms of the anti-Toxoplasma action of CsA and may be instrumental in the rational design of new therapeutic drugs modulating TgCyp activity
ACS Infectious Diseases (2023)   (doi: 10.1021/acsinfecdis.2c00566)
Sis0455 Click on the ikmage to get a larger copy
Deciphering the Second Messenger Processing Mechanism by Standalone CRISPR-Cas Ring Nucleases.
CRISPR-Cas systems comprise an adaptive immune system in bacteria and archaea against foreign mobile genetic elements, such as plasmids and phages, which has constituted a revolution in life sciences. Their discovery and straightforward development into versatile nucleases by guide RNA exchange paved the way for gene modifications à la carte that can be employed in biomedicine and biotechnology.

Type III CRISPR-Cas effector systems detect foreign RNA triggering DNA and RNA cleavage and synthesizing cyclic oligoadenylate molecules (cA) in their Cas10 subunit. cAs act as a second messenger activating auxiliary nucleases, leading to an indiscriminate RNA degradation that can end in cell dormancy or death. Standalone ring nucleases are CRISPR ancillary proteins which downregulate the strong immune response of Type III systems by degrading cA. Two genes with this function (Sis0811 and Sis0455) have been found within the Sulfolobus islandicus (Sis) genome. They code for a long polypeptide composed by a CARF domain fused to an HTH domain (Sis0811 described in Molina et al., Nucleic Acids Research, 2021) and a short polypeptide constituted by a CARF domain with a 40 residue C-terminal insertion (Sis0455). Here, we determine the structure of the apo and substrate bound states of the Sis0455 enzyme, revealing an insertion at the C-terminal region of the CARF domain, which plays a key role closing the catalytic site upon substrate binding. Our analysis reveals the key residues of Sis0455 during cleavage and the coupling of the active site closing with their positioning to proceed with cA4 phosphodiester hydrolysis. A time course comparison of cA4 cleavage between the short, Sis0455, and long ring nucleases, Sis0811, shows the slower cleavage kinetics of the former, suggesting that the combination of these two types of enzymes with the same function in a genome could be an evolutionary strategy to regulate the levels of the second messenger in different infection scenarios.
Nucleic Acids Research (2022)   (doi: 10.1093/nar/gkac923)
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