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Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Structure of the malaria vaccine candidate Pfs48/45 and its recognition by transmission blocking antibodies Kuang-Ting Ko , Frank Lennartz , David Mekhaiel , Bora Guloglu , Arianna Marini , Danielle J. Deuker , Carole A. Long , Matthijs Jore , Kazutoyo Miura , Sumi Biswas , Matthew K. Higgins Nature Communications 13 DOI: 10.1038/s41467-022-33379-6 Diamond Proposal Number(s): [23459] Open Access Show Abstract ▼ Abstract: An effective malaria vaccine remains a global health priority and vaccine immunogens which prevent transmission of the parasite will have important roles in multi-component vaccines. One of the most promising candidates for inclusion in a transmission-blocking malaria vaccine is the gamete surface protein Pfs48/45, which is essential for development of the parasite in the mosquito midgut. Indeed, antibodies which bind Pfs48/45 can prevent transmission if ingested with the parasite as part of the mosquito bloodmeal. Here we present the structure of full-length Pfs48/45, showing its three domains to form a dynamic, planar, triangular arrangement. We reveal where transmission-blocking and non-blocking antibodies bind on Pfs48/45. Finally, we demonstrate that antibodies which bind across this molecule can be transmission-blocking. These studies will guide the development of future Pfs48/45-based vaccine immunogens.	Sep 2022
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Structure and function of a family of tick-derived complement inhibitors targeting properdin Katharina Braunger , Jiyoon Ahn , Matthijs Jore , Steven Johnson , Terence T. L. Tang , Dennis V. Pedersen , Gregers R. Andersen , Susan M. Lea Nature Communications 13 DOI: 10.1038/s41467-021-27920-2 Diamond Proposal Number(s): [12346, 18069] Open Access Show Abstract ▼ Abstract: Activation of the serum-resident complement system begins a cascade that leads to activation of membrane-resident complement receptors on immune cells, thus coordinating serum and cellular immune responses. Whilst many molecules act to control inappropriate activation, Properdin is the only known positive regulator of the human complement system. By stabilising the alternative pathway C3 convertase it promotes complement self-amplification and persistent activation boosting the magnitude of the serum complement response by all triggers. In this work, we identify a family of tick-derived alternative pathway complement inhibitors, hereafter termed CirpA. Functional and structural characterisation reveals that members of the CirpA family directly bind to properdin, inhibiting its ability to promote complement activation, and leading to potent inhibition of the complement response in a species specific manner. We provide a full functional and structural characterisation of a properdin inhibitor, opening avenues for future therapeutic approaches.	Jan 2022
I03-Macromolecular Crystallography	An inhibitor of complement C5 provides structural insights into activation Martin P. Reichhardt , Steven Johnson , Terence Tang , Thomas Morgan , Nchimunya Tebeka , Niko Popitsch , Justin C. Deme , Matthijs M. Jore , Susan Lea Proceedings Of The National Academy Of Sciences 117 DOI: 10.1073/pnas.1909973116 Diamond Proposal Number(s): [18069] Open Access Show Abstract ▼ Abstract: The complement system is a crucial part of innate immune defenses against invading pathogens. The blood-meal of the tick Rhipicephalus pulchellus lasts for days, and the tick must therefore rely on inhibitors to counter complement activation. We have identified a class of inhibitors from tick saliva, the CirpT family, and generated detailed structural data revealing their mechanism of action. We show direct binding of a CirpT to complement C5 and have determined the structure of the C5–CirpT complex by cryoelectron microscopy. This reveals an interaction with the peripheral macro globulin domain 4 (C5_MG4) of C5. To achieve higher resolution detail, the structure of the C5_MG4–CirpT complex was solved by X-ray crystallography (at 2.7 Å). We thus present the fold of the CirpT protein family, and provide detailed mechanistic insights into its inhibitory function. Analysis of the binding interface reveals a mechanism of C5 inhibition, and provides information to expand our biological understanding of the activation of C5, and thus the terminal complement pathway.	Dec 2019
I03-Macromolecular Crystallography	Structural basis for recognition of the malaria vaccine candidate Pfs48/45 by a transmission blocking antibody Frank Lennartz , Florian Brod , Rebecca Dabbs , Kazutoyo Miura , David Mekhaiel , Arianna Marini , Matthijs Jore , Max M. Søgaard , Thomas Jørgensen , Willem A. De Jongh , Robert W. Sauerwein , Carole A. Long , Sumi Biswas , Matthew Higgins Nature Communications 9 DOI: 10.1038/s41467-018-06340-9 Diamond Proposal Number(s): [18069] Open Access Show Abstract ▼ Abstract: The quest to develop an effective malaria vaccine remains a major priority in the fight against global infectious disease. An approach with great potential is a transmission-blocking vaccine which induces antibodies that prevent establishment of a productive infection in mosquitos that feed on infected humans, thereby stopping the transmission cycle. One of the most promising targets for such a vaccine is the gamete surface protein, Pfs48/45. Here we establish a system for production of full-length Pfs48/45 and use this to raise a panel of monoclonal antibodies. We map the binding regions of these antibodies on Pfs48/45 and correlate the location of their epitopes with their transmission-blocking activity. Finally, we present the structure of the C-terminal domain of Pfs48/45 bound to the most potent transmission-blocking antibody, and provide key molecular information for future structure-guided immunogen design.	Sep 2018
I02-Macromolecular Crystallography	Structural basis for therapeutic inhibition of complement C5 Matthijs Jore , Steven Johnson , Devon Sheppard , Natalie Barber , Yang I Li , Miles A Nunn , Hans Elmlund , Susan Lea Nature Structural & Molecular Biology DOI: 10.1038/nsmb.3196 Diamond Proposal Number(s): [9306] Show Abstract ▼ Abstract: Activation of complement C5 generates the potent anaphylatoxin C5a and leads to pathogen lysis, inflammation and cell damage. The therapeutic potential of C5 inhibition has been demonstrated by eculizumab, one of the world's most expensive drugs. However, the mechanism of C5 activation by C5 convertases remains elusive, thus limiting development of therapeutics. Here we identify and characterize a new protein family of tick-derived C5 inhibitors. Structures of C5 in complex with the new inhibitors, the phase I and phase II inhibitor OmCI, or an eculizumab Fab reveal three distinct binding sites on C5 that all prevent activation of C5. The positions of the inhibitor-binding sites and the ability of all three C5–inhibitor complexes to competitively inhibit the C5 convertase conflict with earlier steric-inhibition models, thus suggesting that a priming event is needed for activation.	Mar 2016

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