Prof Neil McDonald
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Overview
Overview
Biography
Neil completed his doctoral training with Professor Tom Blundell at Birkbeck College where he determined structures of the ß-nerve growth factor (NGF) cystine knot and the multi-protein 7S NGF complex. He also uncovered the first evidence of a ligand-induced allosteric changes within the EGFR. He was then awarded a Lucille P. Markey Scholarship for his postdoctoral training to move to the laboratory of Professor Wayne A. Hendrickson in the Department of Biochemistry and Molecular Biophysics, Columbia University, New York. While there he studied the ciliary neurotrophic factor (CNTF) and its receptors and applied multi-wavelength anomalous diffraction (MAD) methods to determine the structure of CNTF, a potential biotherapeutic produced by Regeneron Pharmaceuticals.
Neil was then recruited back to London in 1994 as a Group Leader in order to establish a Structural Biology Laboratory at the ICRF. ICRF became the Cancer Research UK (CR-UK) London Research Institute and is now part of the Francis Crick Institute. Neil holds a joint position at Birkbeck College and was appointed as Professor of Structural Biology in 2006.
His research interests lie in the molecular mechanisms underpinning growth factor signalling at the cell membrane. His group has uncovered molecular mechanisms controlling protein kinase and protein phosphatase activation in both physiological and disease settings. More recently his group have explored: (1) the architecture and regulation of many types of membrane-linked proteins, Rho effector kinases and cell surface receptors (2) the molecular function of the RPEL motif, a multi-valent G-actin-binding signature responding to changes in cellular G-actin levels and (3) the structure determination of several oncology therapeutic targets.
ORCID
0000-0003-0975-6325 -
Supervision and teaching
Supervision and teaching
Teaching
Teaching modules
- Introduction to Molecular Cell Biology (SCBS064H4)
- Evolution and Genetics (SCBS073H5)
- Advanced Topics in Human Disease (SCBS081H6)
- Molecular Biology for Discovery Life Sciences (SCBS096S7)
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Publications
Publications
Article
- Bland, T. and Hirani, N. and Briggs, D. and Rossetto, R. and Ng, K. and McDonald, Neil Q. and Zwicker, D. and Goehring, N.W. (2024) Optimized PAR-2 RING dimerization mediates cooperative and selective membrane binding for robust cell polarity. Embo Journal 43 (15), pp. 3214-3239. ISSN 0261-4189.
- Cobbaut, M. and Parker, P.J. and McDonald, Neil Q. (2023) Into the fold: advances in understanding aPKC membrane dynamics. Biochemical Journal 480 (24), pp. 2037-2044. ISSN 0264-6021.
- Houghton, F.M. and Adams, S.E. and Rios, A.S. and Masino, L. and Purkiss, A.G. and Briggs, D.C. and Ledda, F. and McDonald, Neil Q. (2023) Architecture and regulation of a GDNF-GFRa1 synaptic adhesion assembly. Nature Communications ISSN 2041-1723.
- Cobbaut, M. and McDonald, Neil and Parker, P.J. (2023) Control of atypical PKCι membrane dissociation by tyrosine phosphorylation within a PB1-C1 interdomain interface. Journal of Biological Chemistry 299 (7), ISSN 0021-9258.
- Zhang, L. and Moccia, M. and Briggs, D.C. and Bharate, J.B. and Lakkaniga, N.R. and Knowles, P. and Tran, P. and Kharbanda, A. and Wang, X. and Leung, Y.-K. and Frett, B. and Santoro, M. and McDonald, Neil Q. and Carlomagno, F. and Li, H.-y. (2022) Discovery of N-trisubstituted Pyrimidine Derivatives as Type-I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose. Journal of Medicinal Chemistry 65 (2), pp. 1536-1551. ISSN 0022-2623.
- Adams, S.E. and Purkiss, A.G. and Knowles, P.P. and Nans, A. and Briggs, D.C. and Borg, A. and Earl, C.P. and Goodman, K.M. and Nawrotek, A. and Borg, A.J. and McIntosh, P.B. and Houghton, F.M. and Kjær, S. and McDonald, Neil Q. (2021) A two-site flexible clamp mechanism for RET-GDNF-GFRα1 assembly reveals both conformational adaptation and strict geometric spacing. Structure 29 (7), pp. 694-708.e7. ISSN 0969-2126.
- Parker, P.J. and Brown, S.J. and Calleja, V. and Chakravarty, P. and Cobbaut, M. and Linch, M. and Marshall, J.J.T. and Martini, S. and McDonald, Neil Q. and Soliman, T. and Watson, L. (2021) Equivocal, explicit and emergent actions of PKC isoforms in Cancer. Nature Reviews Cancer 21, pp. 51-63. ISSN 1474-175X.
- Grey, W. and Chauhan, R. and Piganeau, M. and Huerga, E. and Garcia-Albornoz, M. and McDonald, Neil and Bonnet, D. (2020) Activation of the Receptor Tyrosine Kinase, RET, improves long-term Hematopoietic Stem Cell outgrowth and potency. Blood 136 (22), pp. 2535-2547. ISSN 0006-4971.
- Moccia, M. and Frett, B. and Zhang, L. and Lakkaniga, R. and Briggs, D.C. and Chauhan, R. and Brescia, A. and Federico, G. and Santoro, M. and McDonald, Neil Q. and Li, H. and Carlomagno, F. (2020) Bioisosteric discovery of NPA101.3, a second generation RET/VEGFR2 inhibitor optimized for single-agent polypharmacology. Journal of Medicinal Chemistry 63 (9), pp. 4506-4516. ISSN 0022-2623.
- Thomas, A.M. and Brolih, S. and McGouran, J. and El-Sagheer, A.H. and Ptchelkine, D. and Jones, M. and McDonald, Neil Q. and McHugh, P.J. and Brown, T. (2019) Optimised oligonucleotide substrates to assay XPF ERCC1 nuclease activity for the discovery of DNA repair inhibitors. Chemical Communications 55, pp. 11671-11674. ISSN 1359-7345.
- Diring, J. and Mouilleron, S. and McDonald, Neil Q. and Treisman, R. (2019) RPEL family rhoGAPs link Rac/Cdc42 GTP loading to G-actin availability. Nature Cell Biology 21, pp. 845-855. ISSN 1465-7392.
- Elbediwy, A. and Zhang, Y. and Cobbaut, M. and Riou, P. and Tan, R.S. and Roberts, S.K. and Tynan, C. and George, R. and Kjaer, S. and Martin-Fernandez, M.L. and Thompson, B.J. and McDonald, Neil Q. and Parker, P.J. (2019) The Rho-family GEF FARP2 is activated by aPKCiota to control polarity and tight junction formation.. Journal of Cell Science 132 (8), pp. jcs223743. ISSN 0021-9533.
- Yan, W. and Lakkaniga, N.R. and Gunaganti, N. and Lv, F. and Carlomagno, F. and Santoro, M. and McDonald, Neil Q. and Frett, B. and Li, H.-Y. (2018) Insights into Current Tropomyosin Receptor Kinase (TRK) inhibitors: development and clinical application. Journal of Medicinal Chemistry 62 (4), pp. 1731-1760. ISSN 0022-2623.
- Kohno, T. and McDonald, Neil Q. (2018) A secondary RET mutation in the activation loop conferring resistance to vandetanib. Nature Communications 9, pp. 625. ISSN 2041-1723.
- Nakaoku, T. and Kohno, T. and Araki, M. and Niho, S. and Chauhan, R. and Knowles, P.P. and Tsuchihara, K. and Matsumoto, S. and Shimada, Y. and Mimaki, S. and Ishii, G. and Ichikawa, H. and Nagatoishi, S. and Tsumoto, K. and Okuno, Y. and Yoh, K. and McDonald, Neil Q. and Goto, K. (2018) A secondary RET mutation in the activation loop conferring resistance to vandetanib. Nature Communications 9 (1), pp. 625. ISSN 2041-1723.
- Plenker, D. and Riedel, M. and Brägelmann, J. and Dammert, M.A. and Chauhan, R. and Knowles, P.P. and Lorenz, C. and Keul, M. and Bührmann, M. and Pagel, O. and Tischler, V. and Scheel, A.H. and Schütte, D. and Song, Y. and Stark, J. and Mrugalla, F. and Alber, Y. and Richters, A. and Engel, J. and Leenders, F. and Heuckmann, J.M. and Wolf, J. and Diebold, J. and Pall, G. and Peifer, M. and Aerts, M. and Gevaert, K. and Zahedi, R.P. and Buettner, R. and Shokat, K.M. and McDonald, Neil Q. and Kast, S.M. and Gautschi, O. and Thomas, R.K. and Sos, M.L. (2017) Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors. Science Translational Medicine 9 (394), ISSN 1946-6234.
- Plenker, D. and Riedel, M. and Brägelmann, J. and Dammert, M.A. and Chauhan, R. and Knowles, P.K. and Lorenz, C. and Keul, M. and Bührmann, M. and Pagel, O. and Tischler, V. and Scheel, A.H. and Schütte, D. and Song, Y. and Stark, J. and Mrugalla, F. and Alber, Y. and Richters, A. and Engel, J. and Leenders, F. and Heuckmann, J.M. and Wolf, J. and Diebold, J. and Pall, G. and Peifer, M. and Aerts, M. and Gevaert, K. and Zahedi, R.P. and Buettner, R. and Shokat, K.M. and McDonald, Neil Q. and Kast, S.M. and Gautschi, O. and Thomas, R.K. and Sos, M.L. (2017) Mechanistic insight into RET kinase inhibitors targeting the DFG-out conformation in RET-rearranged cancer. Science Translational Medicine 9 (394), ISSN 1946-6234.
- McDonald, Neil Q. (2016) RET functions as a dual-specificity kinase that requires allosteric inputs from juxtamembrane elements. Cell Reports 17 (12), pp. 3319-3332. ISSN 2211-1247.
- McDonald, Neil Q. (2016) aPKC inhibition by Par3 CR3 flanking regions controls substrate access and underpins apical-junctional polarization. Developmental Cell 38 (4), pp. 384-398. ISSN 1534-5807.
- Gabreski, N.A. and Vaghasia, J.K. and Novakova, S.S. and McDonald, Neil Q. and Pierchala, B.A. (2016) Exon skipping in the RET Gene encodes novel isoforms that differentially regulate RET Protein signal transduction. Journal of Biological Chemistry 291 (31), pp. 16249-16262. ISSN 0021-9258.
- Newton, R. and Bowler, K.A. and Burns, E.M. and Chapman, P.J. and Fairweather, E.E. and Fritzl, S.J.R. and Goldberg, K.M. and Hamilton, N.M. and Holt, S.V. and Hopkins, G.V. and Jones, S.D. and Jordan, A.M. and Lyons, A.J. and Nikki March, H. and McDonald, Neil Q. and Maguire, L.A. and Mould, D.P. and Purkiss, A.G. and Small, H.F. and Stowell, A.I.J. and Thomson, G.J. and Waddell, I.D. and Waszkowycz, B. and Watson, A.J. and Ogilvie, D.J. (2016) The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity. European Journal of Medicinal Chemistry 112, pp. 20-32. ISSN 0223-5234.
- Goodman, K.M. and Kjær, S. and Beuron, F. and Knowles, P.P. and Nawrotek, A. and Burns, E.M. and Purkiss, A.G. and George, R. and Santoro, M. and Morris, E.P. and McDonald, Neil Q. (2014) RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association. Cell Reports 18 (6), pp. 1894-1904. ISSN 2211-1247.
- Wang, Z. and Lambden, S. and Taylor, V. and Sujkovic, E. and Nandi, M. and Tomlinson, J. and Dyson, A. and McDonald, Neil Q. and Caddick, S. and Singer, M. and Leiper, J. (2014) Pharmacological inhibition of DDAH1 improves survival, haemodynamics and organ function in experimental septic shock. Biochemical Journal 460 (2), pp. 309-316. ISSN 0264-6021.
- Plaza-Menacho, I. and Barnouin, K. and Goodman, K. and Martínez-Torres, R.J. and Borg, A. and Murray-Rust, J. and Mouilleron, S. and Knowles, P.P. and McDonald, Neil Q. (2014) Oncogenic RET Kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans. Molecular Cell 53 (5), pp. 738-751. ISSN 1097-2765.
- Coulthard, R. and Deans, A.J. and Swuec, P. and Bowles, M. and Costa, A. and West, S.C. and McDonald, Neil Q. (2013) Architecture and DNA recognition elements of the Fanconi Anemia FANCM-FAAP24 Complex. Structure 21 (9), pp. 1648-1658. ISSN 0969-2126.
- Riou, P. and Kjær, S. and Garg, R. and Purkiss, Andrew G. and George, R. and Cain, R.J. and Bineva, G. and Reymond, N. and McColl, B. and Thompson, A.J. and O’Reilly, N. and McDonald, Neil Q. and Parker, P.J. and Ridley, A.J. (2013) 14-3-3 Proteins Interact with a Hybrid Prenyl-Phosphorylation Motif to Inhibit G Proteins. Cell 153 (3), pp. 640-653. ISSN 0092-8674.
- Fadden, A.J. and Schalbetter, S. and Bowles, M. and Harris, R. and Lally, J. and Carr, A.M. and McDonald, Neil Q. (2013) A winged helix domain in human MUS81 binds DNA and modulates the endonuclease activity of MUS81 complexes. Nucleic Acids Research ISSN 0305-1048.
- Mouilleron, S. and Wiezlak, M. and O’Reilly, N. and Treisman, R. and McDonald, Neil Q. (2012) Structures of the Phactr1 RPEL domain and RPEL motif complexes with G-Actin reveal the molecular basis for Actin Binding Cooperativity. Structure 20 (11), pp. 1960-1970. ISSN 0969-2126.
- Bowles, M. and Lally, J. and Fadden, A.J. and Mouilleron, S. and Hammonds, T. and McDonald, Neil Q. (2012) Fluorescence-based incision assay for human XPF-ERCC1 activity identifies important elements of DNA junction recognition. Nucleic Acids Research 40 (13), pp. e101. ISSN 0305-1048.
- Mouilleron, S. and Langer, C.A. and Guettler, S. and McDonald, Neil Q. and Treisman, R. (2011) Structure of a pentavalent G-Actin*MRTF-A complex reveals how G-Actin controls nucleocytoplasmic shuttling of a transcriptional coactivator. Science Signaling 4 (177), pp. ra40. ISSN 1945-0877.
- Boëda, B. and Knowles, P.P. and Briggs, David C. and Murray-Rust, J. and Soriano, E. and Garvalov, B.K. and McDonald, Neil Q. and Way, M. (2011) Molecular recognition of the tes LIM2–3 domains by the actin-related protein arp7A. Journal of Biological Chemistry 286 (13), pp. 11543-11554. ISSN 0021-9258.
- Kjaer, S. and Hanrahan, S. and Totty, N. and McDonald, Neil Q. (2010) Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations. Nature Structural & Molecular Biology 17 (6), pp. 726-731. ISSN 1545-9993.
- Mologni, L. and Rostagno, R. and Brussolo, S. and Knowles, P.P. and Kjaer, S. and Murray-Rust, J. and Rosso, E. and Zambon, A. and Scapozza, L. and McDonald, Neil Q. and Lucchini, V. and Gambacorti-Passerini, C. (2010) Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors. Bioorganic & Medicinal Chemistry 18 (4), pp. 1482-1496. ISSN 1464-3391.
- Kostelecky, B. and Saurin, A.T. and Purkiss, Andrew G. and Parker, P.J. and McDonald, Neil Q. (2009) Recognition of an intra-chain tandem 14-3-3 binding site within PKCepsilon. EMBO Reports 10 (9), pp. 983-989. ISSN 1469-3178.
- Roffey, J. and Rosse, C. and Linch, M. and Hibbert, A. and McDonald, Neil Q. and Parker, P.J. (2009) Protein kinase C intervention: the state of play. Current Opinion in Cell Biology 21 (2), pp. 268-279. ISSN 1879-0410.
- Carlomagno, F. and Guida, T. and Anaganti, S. and Provitera, L. and Kjaer, S. and McDonald, Neil Q. and Ryan, A.J. and Santoro, M. (2009) Identification of tyrosine 806 as a molecular determinant of RET kinase sensitivity to ZD6474. Endocrine-Related Cancer 16 (1), pp. 233-241. ISSN 1351-0088.
- Mouilleron, S. and Guettler, S. and Langer, C.A. and Treisman, R. and McDonald, Neil Q. (2008) Molecular basis for G-actin binding to RPEL motifs from the serum response factor coactivator MAL. The EMBO Journal 27 (23), pp. 3198-3208. ISSN 1460-2075.
- Kirk, R. and Laman, H. and Knowles, P.P. and Murray-Rust, J. and Lomonosov, M. and Meziane, E.K. and McDonald, Neil Q. (2008) Structure of a conserved dimerization domain within the F-box protein Fbxo7 and the PI31 proteasome inhibitor. Journal of Biological Chemistry 283 (32), pp. 22325-22335. ISSN 0021-9258.
- Ciccia, A. and McDonald, Neil Q. and West, S.C. (2008) Structural and functional relationships of the XPF/MUS81 family of proteins. Annual Review of Biochemistry 77, pp. 259-287. ISSN 0066-4154.
- Roces, L. and Knowles, P.P. and Fox, G. and Juanhuix, J. and Scaplehorn, N. and Way, M. and McDonald, Neil Q. (2008) Crystallization and preliminary X-ray diffraction analysis of vaccinia virus H1L phosphatase. Acta Crystallographica Section F F64 (3), pp. 190-192. ISSN 1744-3091.