Cryo-tomography and 3D Electron Diffraction Reveal the Polar Habit and Chiral Structure of the Malaria Pigment Crystal Hemozoin
- Author(s)
- Paul Benjamin Klar, David Geoffrey Waterman, Tim Gruene, Debakshi Mullick, Yun Song, James Boris Gilchrist, C. David Owen, Wen Wen, Idan Biran, Lothar Houben, Neta Regev-Rudzki, Ron Dzikowski, Noa Marom, Lukas Palatinus, Peijun Zhang, Leslie Leiserowitz, Michael Elbaum
- Abstract
Detoxification of heme in Plasmodium depends on its crystallization into hemozoin. This pathway is a major target of antimalarial drugs. The crystalline structure of hemozoin was established by X-ray powder diffraction using a synthetic analog, β-hematin. Here, we apply emerging methods of in situ cryo-electron tomography and 3D electron diffraction to obtain a definitive structure of hemozoin directly from ruptured parasite cells. Biogenic hemozoin crystals take a striking polar morphology. Like β-hematin, the unit cell contains a heme dimer, which may form four distinct stereoisomers: two centrosymmetric and two chiral enantiomers. Diffraction analysis, supported by density functional theory analysis, reveals a selective mixture in the hemozoin lattice of one centrosymmetric and one chiral dimer. Absolute configuration has been determined by morphological analysis and confirmed by a novel method of exit-wave reconstruction from a focal series. Atomic disorder appears on specific facets asymmetrically, and the polar morphology can be understood in light of water binding. Structural modeling of the heme detoxification protein suggests a function as a chiral agent to bias the dimer formation in favor of rapid growth of a single crystalline phase. The refined structure of hemozoin should serve as a guide to new drug development.
- Organisation(s)
- Department of Inorganic Chemistry, Core Facility Crystal Structure Analysis
- External organisation(s)
- Jacobs Universität Bremen, Czech Academy of Sciences, Rutherford Appleton Laboratory, Weizmann Institute of Science, Diamond Light Source Ltd, Carnegie Mellon University, Hebrew University Jerusalem, University of Oxford
- Journal
- ACS Central Science
- Volume
- 10
- Pages
- 1504-1514
- No. of pages
- 11
- ISSN
- 2374-7943
- DOI
- https://doi.org/10.1021/acscentsci.4c00162
- Publication date
- 07-2024
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 106002 Biochemistry, 103006 Chemical physics, 105113 Crystallography
- ASJC Scopus subject areas
- General Chemistry, General Chemical Engineering
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/c2825ff0-fa1f-45aa-9885-ccb9c728a085