The Relevance of Structural Biology in Studying Molecules Involved in Parasite–Host Interactions: Potential for Designing New Interventions

Abstract

1Mason et al. Structures of parasite proteinsNew interventions against infectious diseases require a detailed knowledge and understanding of pathogen-host interactions and pathogeneses at the molecular level. The combination of the considerable advances in systems biology research with methods to explore the structural biology of molecules is poised to provide new insights into these areas. Importantly, exploring threedimensional structures of proteins is central to understanding disease processes, and establishing structure-function relationships assists in identification and assessment of new drug and vaccine targets. Frequently, the molecular arsenal deployed by invading pathogens, and in particular parasites, reveals a common theme whereby families of proteins with conserved three-dimensional folds play crucial roles in infectious processes, but individual members of such families show high levels of specialisation which is often achieved through grafting particular structural features onto the shared overall fold. Accordingly, the applicability of predictive methodologies based on the primary structure of proteins or genome annotations is limited, particularly when thorough knowledge of molecular level mechanisms is required. Such instances exemplify the need for experimental threedimensional structures provided by protein crystallography, which remain an essential component of this area of research. In the present article, we review two examples of key protein families recently investigated in our laboratories, which could represent intervention targets in the metabolome or secretome of parasites. IntroductionInfectious diseases caused by eukaryotic pathogens represent a major disease burden to humans world-wide. In the absence of effective preventative approaches and new intervention strategies, this burden is likely to increase further, [1,2] compounded by food and water shortages, economic crises, wars and climate change, particularly in disadvantaged countries. In addition, there is evidence of increasing problems with resistance in pathogens against a broad range of chemotherapeutic agents, compromising the treatment of infectious diseases. [3] Moreover, in spite of major efforts, there are very few examples of success in developing new drugs and vaccines against eukaryotic pathogens, [4,5] indicating that alternative methods are needed at a time of major advances in molecular and computer technologies. In our opinion, the development of new treatments requires a detailed understanding of pathogens, host interactions and the molecular processes of disease. For instance, knowledge of the three-dimensional structures of proteins with pivotal roles in disease, and the probing of their underlying biology are crucial for understanding the pathogenesis. Through establishing the relevant structure-function relationships, one can elucidate how individual proteins function, so that new ways of disrupting relevant pathways can be found, in order to facilitate the identification of new drug and vaccine targets. ...

Bioinformatics Applications on Cryptosporidium Research: A Review

“…Moreover, binding affinity evaluation is a must to be coupled with molecular docking for getting an accurate assessment on a virtual screening of the particular protein target. Interestingly, it can possibly be promising in the development of more suitable anti-Cryptosporidium drugs in future [67][68][69][70][71][72] .…”

The barber's pole worm CAP protein superfamily — A basis for fundamental discovery and biotechnology advances

“…Qian et al, 2011;Asojo et al, 2011;Mason et al, 2014a). Consequently, future studies investigating particular Hc-CAP proteins should include the experimental determination of three-dimensional structures.…”

International Year of Crystallography

“…[9] Professor We are particularly pleased with the response of the macromolecular crystallographic community, which has also contributed on a wide range of topics to this special issue. Several papers describe crystallographic studies of potential drug targets and structure-based drug design efforts to find medicines relevant to different disorders: Peter Colman for flu virus infection and cancer, [10] Michael Parker and colleagues for mental disorders and inflammatory diseases, [11] Andreas Hofmann and colleagues for parasite infections, [12] Helen Blanchard and colleagues for cancer, and inflammatory and heart diseases, [13] and Julia Archbold and colleagues for bacterial infections. [14] The remaining papers discuss different methodologies relevant to macromolecular crystallography: Fasséli Coulibaly and colleagues reflect on their experience with microcrystallography, [15] Emily Golden and Alice Vrielink take a look at recent advances in neutron crystallography, [16] Sandro Ataide and colleagues discuss challenges of crystallography with RNA and its complexes, [17] Lachlan Casey and colleagues examine the application of small-angle X-ray scattering (SAXS) to macromolecules, [18] Charlie Bond and colleagues describe an interesting effort to engineer a protein with reduced ability to crystallise, [19] and Janet Newman and colleagues propose standards to enable mining of macromolecular crystallisation data.…”