糖心原创

School of Pharmacy

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Jonas Emsley

Professor of Macromolecular Crystallography, Faculty of Science

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Biography

I have a BSc in Biochemistry and Genetics from the 糖心原创 and gained my PhD from Birkbeck College, University of London under the supervision of Sir Tom Blundell.

I was awarded a Fellowship from the Wellcome Trust and appointed to a lectureship at the University of Leicester Biochemistry Department in 2000. I was promoted to Reader in 2004 and moved to the 糖心原创 to found the Crystallography Laboratory which is within the Medicinal Chemistry and Structural Biology Research Division of the School of Pharmacy.

Research Summary

Research interests include determining protein structures and studying the structure/function of complexes formed with drugs and natural ligands. Key developments in recent years includes (i) Determination of the first structure of an integrin/collagen complex. This structure revealed the molecular basis of the contacts formed between cells and the extracellular matrix. (ii) Determination of the platelet receptor glycoprotein Ib extracellular domain and von Willebrand factor A1 domain structures (iii) determination of the coagulation factor xi structure. These proteins are vital to normal platelet adhesion and hemostatic function. We also have collaborative interests in determining structures of protein complexes formed with anti-cancer and anti-thrombosis inhibitors. These structures provide scaffolds which can pave the way for design of improved therapeutic agents.

The structural biology laboratory utilises a variety of techniques including Protein Crystallography, Cryo-electron Microscopy and associated techniques such as Isothermal Titration Calorimetry, which are then combined with functional studies or serve as a basis for structure-based drug design.

Memberships of Committees and Professional Bodies

  • Member of the International Society of Thrombosis and Haemostasis
  • Member of Biochemical Society
  • Member of British Crystallographic Association

Teaching

  • Lectures in Medicinal Chemistry and Macromolecular Structure
  • Lectures in Cardiovascular medicine

Selected Publications

  • LI C, VOOS KM, PATHAK M, HALL G, MCCRAE KR, DREVENY I, LI R and EMSLEY J, 2019. Journal of thrombosis and haemostasis : JTH. (In Press.)
  • PATHAK M, MANNA R, LI C, KAIRA BG, HAMAD BK, BELVISO BD, BONTURI CR, DREVENY I, FISCHER PM, DEKKER LV, OLIVA MLV and EMSLEY J, 2019. Acta crystallographica. Section D, Structural biology. 75(Pt 6), 578-591
  • PETRI A, KIM HJ, XU Y, DE GROOT R, LI C, VANDENBULCKE A, VANHOORELBEKE K, EMSLEY J and CRAWLEY JTB, 2019. Nature communications. 10(1), 3781
  • MORGAN J, SALEEM M, NG R, ARMSTRONG C, WONG SS, CAULTON SG, FICKLING A, WILLIAMS HEL, MUNDAY AD, L脫PEZ JA, SEARLE MS and EMSLEY J, 2019. Blood advances. 3(9), 1450-1459

Past Research

Enzyme's 'molecular scissors' cut out fatal blood clot risk

New research highlights how an essential enzyme works to prevent dangerous clots

By stopping bleeding and allowing wounds to heal, our blood's ability to clot is a vital part of how the body rebuilds and recovers following an injury. In many diseases clots can continue to grow and prevent blood from flowing properly, leading to serious complications.

In a new study published 22/08/19 in Nature Communications, researchers from the 糖心原创, and have revealed fresh insights as to why this important biological process can sometimes go awry.

The findings show how a crucial enzyme in our blood, known as ADAMTS13, works like a pair of molecular scissors to carefully cut back the clotting effects of a key protein, von Willebrand factor (VWF). By resolving the crystal structure of the functional domains of ADAMTS13, the research reveals how after binding VWF, the enzyme must change its shape to open the active site and in turn specifically accommodate the cleavage site in VWF.

Cutting clot risk

When blood vessels are damaged by a cut or by other types of vascular injury, VWF in blood plasma binds to the site of damage and unravels to form long protein strings that specifically capture specialised blood cells (platelets) to the site of injury. This serves to stem the flow of blood and reduce bleeding. If VWF is deficient, patients bleed. Conversely, if VWF is not regulated properly by ADAMTS13, it can result in thrombotic events such as heart attack, stroke or the life-threatening blood disorder thrombotic thrombocytopenic purpura (TTP). This is because when VWF is produced, it is hypersensitive to blood flow. Therefore, if VWF function is not adequately controlled this leads to excessive platelet clumping and clot formation.

While demonstrated the important role of ADAMTS13 in regulating VWF, the findings published in Nature Communications pinpoint the specific molecular mechanisms underlying this crucial relationship between enzyme and substrate. Based on the study team's exploration of the enzyme's crystal structure, we now know that ADAMTS13's unique butterfly-like shape allows it to bind specifically to VWF when it recognises the protein in our blood. Once bound, the enzyme acts as a pair of molecular scissors, trimming down VWF's sticky protein strings and thereby preventing it from amassing blood cells excessively into a dangerous clot. Once ADAMTS13 has tailored the clotting effects of the VWF, it reverts into a latent form which stops it from degrading other important proteins in our body. In this form, the enzyme also becomes resistant to inhibitors, allowing it to exist in our blood for longer.

'Feel the Force' of blood movement

VWF forms long protein strings which act like velcro and recognise areas of the blood vessels that need repairing. VWF has the remarkable property that it folds up into an inactive form, but it is able to 'feel the force' of the blood moving around it and in so doing alter its shape which changes it into an adhesive protein capable of capturing blood platelets, leading to it being described as the 'Jedi Knight' of the blood stream (quote from Tim Springer, Harvard University).

The new study has revealed the butterfly shape of this molecular scissor that cleaves the VWF strings down to size and enzyme activation is driven by force induced sensing and unfolding of VWF which is able to unpick the lock of the latent form of the ADAMTS13 enzyme active site through a mechanism that remains to be discovered.

New treatments for blood disorders

The study team are now keen to explore how this new knowledge of ADAMTS13's highly-specialised structure can be used to develop treatments for strokes, heart attacks and rare blood disorders.

Professor Jonas Emsley (School of Pharmacy, Nottingham University) commented: "As the ADAMTS13 has a critical role in shaping VWF and guiding its sensitivity to force, ADAMTS13 may be viewed as the 'Jedi master' enzyme of the blood. The pharmaceutical industry will benefit from this research through the potential to rationally modify and develop ADAMTS13 as a therapeutic agent. To do this, it is essential to understand its structure and function. To know which parts of the molecule are important (or redundant), and what the limiting steps in its production and function are central to facilitating this and design means to avoid recognition by the immune system,"

"The pharmaceutical industry is currently running trials of recombinant ADAMTS13 in the setting of thrombotic thrombocytopenic purpura (TTP). Work from this proposal will provide a molecular structure of ADAMTS13 in isolation and in complex with its substrate. Importantly, this will provide the opportunity to improve the ADAMTS13 molecule through targeted modification to reduce immunogenicity in inherited TTP, reduce inhibition and clearance in acquired TTP, and to reduce ADAMTS13 clearance and so prolong plasma half-life (improving bioavailability, reducing dosing/frequency of dosing)."

Petri A, Kim HJ, Xu Y, de Groot R, Li C, Vandenbulcke A, Vanhoorelbeke K, Emsley J, Crawley JTB.

Nat Commun. 2019 Aug 22;10(1):3781. doi: 10.1038/s41467-019-11474-5.

PMID:31439947

Future Research

We utilise protein crystallography to investigate molecular structure and analyse protein-ligand and drug-bound complexes. Recent breakthroughs in new cameras and powerful computational approaches for utilising Cryo-electron microscopy (Cryo-EM) have enabled us to determine, at atomic resolution, the architectures of larger molecular machines. We are also using pioneering novel chemical structural biology approaches to target proteins with small molecules or peptides. Therapeutic areas of interest are cardiovascular disease, cancer, neurodegeneration and infectious diseases. A main research focus area are proteases, an important family of proteins. Although proteases were originally studied as the molecular scissors of nonspecific protein catabolism, our view of proteases has considerably expanded and now protease research is key to understanding biological processes as diverse as brain function, respiratory biology, infection and immunity, cardiovascular function, cell growth and death. The protease family represents 2% of all genes present in the human genome and is at the forefront of discovering new medicines. Examples being currently studied are serine proteases from the blood plasma such as Coagulation Factor XI, FXII and plasma kallikrein, metalloproteinases such as ADAMTS13 and cysteine proteases such as the majority of deubiquitinating enzymes.

  • LI C, VOOS KM, PATHAK M, HALL G, MCCRAE KR, DREVENY I, LI R and EMSLEY J, 2019. Journal of thrombosis and haemostasis : JTH. (In Press.)
  • PATHAK M, MANNA R, LI C, KAIRA BG, HAMAD BK, BELVISO BD, BONTURI CR, DREVENY I, FISCHER PM, DEKKER LV, OLIVA MLV and EMSLEY J, 2019. Acta crystallographica. Section D, Structural biology. 75(Pt 6), 578-591
  • PETRI A, KIM HJ, XU Y, DE GROOT R, LI C, VANDENBULCKE A, VANHOORELBEKE K, EMSLEY J and CRAWLEY JTB, 2019. Nature communications. 10(1), 3781
  • MORGAN J, SALEEM M, NG R, ARMSTRONG C, WONG SS, CAULTON SG, FICKLING A, WILLIAMS HEL, MUNDAY AD, L脫PEZ JA, SEARLE MS and EMSLEY J, 2019. Blood advances. 3(9), 1450-1459
  • SCHMAIER AH, EMSLEY J, FEENER EP, GAILANI D, GOVERS-RIEMSLAG JWP, KAPLAN AP, MAAS C, MORRISSEY JH, RENN脡 T, SIDELMANN JJ and MEIJERS JCM, 2019. Journal of thrombosis and haemostasis : JTH. (In Press.)
  • KARDEBY C, F脛LKER K, HAINING EJ, CRIEL M, LINDKVIST M, BARROSO R, P脜HLSSON P, LJUNGBERG LU, TENGDELIUS M, RAINGER GE, WATSON S, EBLE JA, HOYLAERTS MF, EMSLEY J, KONRADSSON P, WATSON SP, SUN Y and GRENEG脜RD M, 2019. Blood advances. 3(3), 275-287
  • WARD SJ, GRATTON HE, INDRAYUDHA P, MICHAVILA C, MUKHOPADHYAY R, MAURER SK, CAULTON SG, EMSLEY J and DREVENY I, 2018. The Journal of biological chemistry. 293(45), 17362-17374
  • SALU BR, PANDO SC, BRITO MV, MEDINA AF, ODEI-ADDO F, FROST C, NAUDE R, SAMPAIO MU, EMSLEY J, MAFFEI FHA and OLIVA MLV, 2018. Platelets. 30(3), 305-313
  • PATHAK M, KAIRA BG, SLATER A and EMSLEY J, 2018. Frontiers in medicine. 5, 66
  • MOHAMMED BM, IVANOV I, MATAFONOV A, EMSLEY J and GAILANI D, 2018. Research and practice in thrombosis and haemostasis. 2(1), 168-173
  • IVANOV I, MATAFONOV A, SUN MF, CHENG Q, DICKESON SK, VERHAMME IM, EMSLEY J and GAILANI D, 2017. Blood. 129(11), 1527-1537
  • HAMAD BK, PATHAK M, MANNA R, FISCHER PM, EMSLEY J and DEKKER LV, 2017. Journal of thrombosis and haemostasis : JTH. (In Press.)
  • MOHAMMED BM, MATAFONOV A, IVANOV I, SUN MF, CHENG Q, DICKESON SK, LI C, SUN D, VERHAMME IM, EMSLEY J and GAILANI D, 2017. Thrombosis research. 161, 94-105
  • DREES SL, LI C, PRASETYA F, SALEEM M, DREVENY I, WILLIAMS P, HENNECKE U, EMSLEY J and FETZNER S, 2016. J Biol Chem. 291(13), 6610-24
  • WONG SS, 脴STERGAARD S, HALL G, LI C, WILLIAMS PM, STENNICKE H and EMSLEY J, 2016. Blood. 127(23), 2915-23
  • PATHAK M, WILMANN P, AWFORD J, LI C, HAMAD BK, FISCHER PM, DREVENY I, DEKKER LV and EMSLEY J, 2015. Journal of Thrombosis and Haemostasis. 13(4), 580-591
  • GAILANI, DAVID, GENG, YIPENG, VERHAMME, INGRID, SUN, MAO-FU, BAJAJ, S. PAUL, MESSER, AMANDA and EMSLEY, JONAS, 2014. THROMBOSIS RESEARCH. 133, S48-S51
  • CHEN J, ZHOU H, DIACOVO A, ZHENG XL, EMSLEY J and DIACOVO TG, 2014. Blood. 124(25), 3799-807
  • OTHMAN M and EMSLEY J, 2014. Seminars in thrombosis and hemostasis. 40(2), 146-50
  • PATHAK, M., WONG, S.S., DREVENY, I. and EMSLEY, J., 2013. Thrombosis and Haemostasis. 110(3), 423-433
  • ILANGOVAN, A., FLETCHER, M., RAMPIONI, G., PUSTELNY, C., RUMBAUGH, K., HEEB, S., C脕MARA, M, TRUMAN, A., CHHABRA, S.R., EMSLEY, J. and WILLIAMS, P., 2013. PLoS Pathogens. 9(7), e1003508
  • EDWARDS, JOHN M., LONG, JED, DE MOOR, CORNELIA H., EMSLEY, JONAS and SEARLE, MARK S., 2013. NUCLEIC ACIDS RESEARCH. 41(14), 7153-7166
  • GENG, Y., VERHAMME, I. M., SUN, M. F., BAJAJ, S. P., EMSLEY, J. and GAILANI, D., 2013. JOURNAL OF THROMBOSIS AND HAEMOSTASIS. 11(7), 1374-1384
  • OTHMAN, MAHA, KAUR, HARMANPREET and EMSLEY, JONAS, 2013. SEMINARS IN THROMBOSIS AND HEMOSTASIS. 39(6), 663-673
  • ENAYAT S, RAVANBOD S, RASSOULZADEGAN M, JAZEBI M, TARIGHAT S, ALA F, EMSLEY J and OTHMAN M, 2012. Thrombosis and haemostasis. 108(5), 946-54
  • BYRNE, C., MCEWAN, P.A., EMSLEY, J., FISCHER, P.M. and CHAN, W.C., 2011. Chemical Communications. 47(9), 2589-2591
  • HALL, GARETH, BRADSHAW, TRACEY D, LAUGHTON, CHARLES A, STEVENS, MALCOLM F and EMSLEY, JONAS, 2011. Protein science : a publication of the Protein Society. 20(1), 210-5
  • EDWARDS, J., MALAURIE, E., KONDRASHOV, A., LONG, J., DE MOOR, C.H., SEARLE, M.S. and EMSLEY, J., 2011. Nucleic Acids Research. 39(19), 8638-8650
  • MCEWAN, P.A., YANG, W., CARR, K.H., MO, X., ZHENG, X., LI, R. and EMSLEY, J., 2011. Blood. 118(19), 5292-5301
  • LUKEN, B.M., WINN, L.Y.N., EMSLEY, J., LANE, D.A. and CRAWLEY, J.T.B., 2010. Brief report The importance of vicinal cysteines, C1669 and C1670, for von Willebrand factor A2 domain function BLOOD -NEW YORK-. VOL 115(NUMB 23), 4910-4913
  • EMSLEY, JONAS, MCEWAN, PAUL A and GAILANI, DAVID, 2010. Blood. 115(13), 2569-77
  • HALL, G. and EMSLEY, J., 2010. Protein Science. 19(9), 1807-1811
  • GINGRAS, ALEXANDRE R, BATE, NEIL, GOULT, BENJAMIN T, PATEL, BIPIN, KOPP, PETRA M, EMSLEY, JONAS, BARSUKOV, IGOR L, ROBERTS, GORDON C K and CRITCHLEY, DAVID R, 2010. The Journal of biological chemistry. 285(38), 29577-87
  • WADELIN, F., FULTON, J., MCEWAN, P.A., SPRIGGS, K.A., EMSLEY, J. and HEERY, D.M., 2010. Molecular Cancer. 27(9), 226
  • GAILANI D, SUN M, CHENG Q, MATAFONOV A, TUCKER EI, GRUBER A and EMSLEY J, 2010. Blood. 116(7), 1185-6; author reply 1186-7
  • GINGRAS, ALEXANDRE R, ZIEGLER, WOLFGANG H, BOBKOV, ANDREY A, JOYCE, M GORDON, FASCI, DOMENICO, HIMMEL, MIRKO, ROTHEMUND, SVEN, RITTER, ANETT, GROSSMANN, J G脺NTER, PATEL, BIPIN, BATE, NEIL and GOULT,, 2009. The Journal of biological chemistry. 284(13), 8866-76
  • MO, X, NGUYEN, N X, MCEWAN, P A, ZHENG, X, L脫PEZ, J A, EMSLEY, J and LI, R, 2009. Journal of thrombosis and haemostasis : JTH. 7(9), 1533-40
  • MCEWAN, P.A., ANDREWS, R.K. and EMSLEY, J., 2009. Blood. 114(23), 4883-4885
  • HOOLEY, ELIZABETH, PAPAGRIGORIOU, EVANGELOS, NAVDAEV, ALEXEI, PANDEY, AMIT V, CLEMETSON, JEANNINE M, CLEMETSON, KENNETH J and EMSLEY, JONAS, 2008. The crystal structure of the platelet activator aggretin reveals a novel (alphabeta)2 dimeric structure. Biochemistry. 47(30), 7831-7
  • ZIEGLER, WOLFGANG H, GINGRAS, ALEX R, CRITCHLEY, DAVID R and EMSLEY, JONAS, 2008. Integrin connections to the cytoskeleton through talin and vinculin. Biochemical Society transactions. 36(Pt 2), 235-9
  • BRIGGS, G.S., MCEWAN, P.A., YU, J., MOORE, T., EMSLEY, J. and LLOYD, R.G., 2007. Journal of Biological Chemistry. 282(17), 12353-12357
  • ROSADO, C.J., BUCKLE, A.M., LAW, R.H.P., BUTCHER.R.E., KAN, W.-T., BIRD, C.H., UNG, K., BROWNE, K.A., BARAN, K., BASHTANNYK-PUHALOVICH, T.A., FAUX, N.G., WONG, W., PORTER, C.J., PIKE, R.N., ELLISDON, A.M., PEARCE, M.C., BOTTOMLEY, S.P., EMSLEY, J., SMITH, A.I., ROSSJOHN J., HARTLAND, E.L., VOSKOBOINIK, I., TRAPANI, J.A., BIRD, P.I., DUNSTONE, M.A. and WHISSTOCK, J.C., 2007. Science. 317(5844), 1548-1551
  • HOOLEY, E, MCEWAN, P A and EMSLEY, J, 2007. Journal of Thrombosis and Haemostasis: JTH. 5(12), 2461-6
  • PAPAGRIGORIOU, E., MCEWAN, P.A., WALSH, P.N. and EMSLEY, J., 2006. Nature Structural & Molecular Biology. 13(6), 557-558
  • PATEL, B., GINGRAS, A. R., BOBKOV, A. A., FUJIMOTO, L. M., ZHANG, M., LIDDINGTON, R. C., MAZZEO, D., EMSLEY, J., ROBERTS, G. C. K. and BARSUKOV, I. L., 2006. Journal of Biological Chemistry. VOL 281(NUMB 11), 7458-7497
  • GINGRAS, A.R., VOGEL, K.P., STEINHOFF, H.J., ZIEGLER, W.H., PATEL, B., EMSLEY, J., CRITCHLEY, D.R., ROBERTS, G.C. and BARSUKOV, I.L., 2006. Biochemistry. 45(6), 1805-17 (In Press.)
  • FILLINGHAM, I., GINGRAS, A.R., PAPAGRIGORIOU, E., PATEL, B., EMSLEY, J., CRITCHLEY, D.R., ROBERTS, G.C.K. and BARSUKOV, I.L., 2005. Structure. 13(1), 65-74
  • GINGRAS, A.R., ZIEGLER, W.H., FRANK, R., BARSUKOV, I.L., ROBERTS, G.C.K., CRITCHLEY, D.R. and EMSLEY, J., 2005. Journal of Biological Chemistry. 280(44), 37217-37224
  • PAPAGRIGORIOU, E., GINGRAS, A.R., BARSUKOV, I.L., BATE, N., FILLINGHAM, I.J., PATEL, B., FRANK, R., ZIEGLER, W.H., ROBERTS, G.C.K., CRITCHLEY, D.R. and EMSLEY, J., 2004. EMBO Journal. 23(15), 2942-2951
  • EMSLEY, JONAS, KNIGHT, C GRAHAM, FARNDALE, RICHARD W and BARNES, MICHAEL J, 2004. Journal of Molecular Biology. 335(4), 1019-28
  • BAGLIA, F. A., SHRIMPTON, C. N., EMSLEY, J., KITAGAWA, K., RUGGERI, Z. M., LOPEZ, J. A. and WALSH, P. N., 2004. Journal of Biological Chemistry. VOL 279(NUMB 47), 49323-49329
  • UFF, S., CLEMETSON, J.M., HARRISON, T., CLEMETSON, K.J. and EMSLEY, J., 2002. Journal of Biological Chemistry. 277(38), 35657-35663

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