Dr Alisa Glukhova, Lab Head | WEHI Researcher Profile

Q: Structural basing for Wnt acylation

Wnt proteins are essential for many cell processes, including differentiation and migration. Porcupine (PORCN) is a transmembrane protein that modifies all Wnts with a fatty molecule, which is crucial for Wnt secretion and activity. Because of this, PORCN inhibitors show potential for treating various types of human cancers. Using cryo-EM, we achieved the highest resolution PORCN structure (2.5 Å) with a small molecule inhibitor. This student project will expand upon our PORCN work and employ cryo-EM to determine the PORCN-Wnt complex structure, aiming to understand Wnt modification by PORCN at the molecular level.

Q: Mechanisms of Wnt secretion and transport

Wnt proteins play a vital role in various cell processes, including differentiation and migration. As lipophilic molecules, Wnts require carrier proteins to maintain solubility outside cells. The exact interaction mechanism between Wnts and these carrier proteins remains unknown. Additionally, other extracellular proteins regulate Wnt signaling through interactions and modifications of Wnt proteins. Understanding these processes and their regulation will ultimately help discover new therapeutic targets.This project will employ cryo-electron microscopy, x-ray crystallography, and complementary techniques to investigate Wnt complexes with extracellular proteins, such as afamin, serum albumin, and Norrin, to enhance understanding of their interactions and regulatory functions.

Q: Mechanism of Fzd receptor activation by Wnt

Wnt signaling is initiated by Wnt proteins when they interact with their receptors, Frizzled, and co-receptors. Although this step is crucial for understanding Wnt signaling biology and developing new therapies, the molecular details remain elusive. Existing structural information on individual steps is incomplete, and the full picture is yet to be uncovered. This ambitious project aims to employ structural biology and complementary techniques to gain insights into how Wnt binding leads to Frizzled activation and signal transmission into the cell.

Q: Understanding the biology of 12-lipoxygenase

The enzyme 12-Lipoxygenase (12-LOX) is a promising drug target for preventing platelet activation and thrombosis. ML355, a 12-LOX inhibitor, has shown potential in treating heparin-induced thrombocytopenia. In collaboration with Thal, Holman, and Holinstat laboratories, we were the first to determine the high-resolution structures of human 12-LOX, including structures with the clinically relevant inhibitor ML355 and an endogenous acyl-coenzyme A. This project aims to build upon our structural studies to further understand 12-LOX biology, including its oligomeric states, catalysis, and membrane binding, and to gain insights into a new generation of 12-LOX inhibitors.

About

Dr Alisa Glukhova is a laboratory head in the Structural Biology division at WEHI and a Senior Research Fellow in the Department of Biochemistry and Pharmacology at the University of Melbourne. She earned her PhD in Chemical Biology in 2014 from the University of Michigan, where she worked on solving structures of lipid-modifying enzymes using x-ray crystallography. During her postdoctoral training at Monash Institute of Pharmaceutical Sciences, she used x-ray crystallography, cryo-electron microscopy, and pharmacology techniques to study different G protein-coupled receptors.

Since joining WEHI in 2020, Alisa has focused on understanding the structural and biochemical aspects of the Wnt signalling pathway, an important pharmacological target for treating many cancers. Using structural biology, her team captures snapshots of different stages in the Wnt signalling cascade to understand the atomic picture and gain insights into various aspects of signal transmission through Wnt pathways. Key areas of interest include Wnt acylation by acyl-transferase Porcupine, Wnt secretion and transport outside cells, and the initiation of the Wnt signalling cascade through Wnt interactions with its receptors, Frizzled, and co-receptors. Alisa ultimately hopes to use this atomic-level information to develop better therapies for devastating human conditions, such as cancer.

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Selected publications from Dr Alisa Glukhova

Callegari S, Kirk NS, Gan ZY, Dite T, Cobbold SA, Leis A, Dagley LF, Glukhova A, Komander D. Structure of human PINK1 at a mitochondrial TOM-VDAC array. Science. 2025;388(6744):10.1126/science.adu6445

Bennetts FM, Venugopal H, Glukhova A, Mobbs JI, Ventura S, Thal DM. Structural insights into the human P2X1 receptor and ligand interactions. Nature Communications. 2024;15(1):10.1038/s41467-024-52776-7

Meng Y, Garnish SE, Davies KA, Black KA, Leis AP, Horne CR, Hildebrand JM, Hoblos H, Fitzgibbon C, Young SN, Dite T, Dagley LF, Venkat A, Kannan N, Koide A, Koide S, Glukhova A, Czabotar PE, Murphy JM. Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization. Nature Communications. 2023;14(1):10.1038/s41467-023-42255-w

Mobbs JI, Black KA, Tran M, Burger WAC, Venugopal H, Holman TR, Holinstat M, Thal DM, Glukhova A. Cryo-EM structures of human arachidonate 12S-lipoxygenase bound to endogenous and exogenous inhibitors. Blood. 2023;142(14):10.1182/blood.2023020441

Burger WAC, Pham V, Vuckovic Z, Powers AS, Mobbs JI, Laloudakis Y, Glukhova A, Wootten D, Tobin AB, Sexton PM, Paul SM, Felder CC, Danev R, Dror RO, Christopoulos A, Valant C, Thal DM. Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR. Nature Communications. 2023;14(1):10.1038/s41467-023-41199-5

Tran M, Yang K, Glukhova A, Holinstat M, Holman T. Inhibitory Investigations of Acyl-CoA Derivatives against Human Lipoxygenase Isozymes. International Journal of Molecular Sciences. 2023;24(13):10.3390/ijms241310941

Vuckovic Z, Wang J, Pham V, Mobbs JI, Belousoff MJ, Bhattarai A, Burger WA, Thompson G, Yeasmin M, Nawaratne V, Leach K, van der Westhuizen ET, Khajehali E, Liang Y-L, Glukhova A, Wootten D, Lindsley CW, Tobin A, Sexton P, Danev R, Valant C, Miao Y, Christopoulos A, Thal DM. Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics. eLife. 2023;12:10.7554/elife.83477

Zhang L, Mobbs JI, May LT, Glukhova A, Thal DM. The impact of cryo-EM on determining allosteric modulator-bound structures of G protein-coupled receptors. Current Opinion in Structural Biology. 2023;79:10.1016/j.sbi.2023.102560

Pymm P, Redmond SJ, Dolezal O, Mordant F, Lopez E, Cooney JP, Davidson KC, Haycroft ER, Tan CW, Seneviratna R, Grimley SL, Purcell DFJ, Kent SJ, Wheatley AK, Wang L-F, Leis A, Glukhova A, Pellegrini M, Chung AW, Subbarao K, Uldrich AP, Tham W-H, Godfrey DI, Gherardin NA. Biparatopic nanobodies targeting the receptor binding domain efficiently neutralize SARS-CoV-2. iScience. 2022;25(11):10.1016/j.isci.2022.105259

Gan ZY, Callegari S, Cobbold SA, Cotton TR, Mlodzianoski MJ, Schubert AF, Geoghegan ND, Rogers KL, Leis A, Dewson G, Glukhova A, Komander D. Publisher Correction: Activation mechanism of PINK1. Nature. 2022;603(7903):10.1038/s41586-022-04591-7

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Lab research projects

Structural basing for Wnt acylation

Mechanisms of Wnt secretion and transport

Mechanism of Fzd receptor activation by Wnt

Understanding the biology of 12-lipoxygenase

Student research projects

AI design of molecular binders against the Wnt signalling pathway

Honours/PhD and Graduate Research Masters

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AI design of molecular binders against the Wnt signalling pathway

Honours/PhD and Graduate Research Masters

More information

View all student research projects

Dr Alisa Glukhova

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