Optimizing the refinement of merohedrally twinned P61 HIV-1 protease-inhibitor cocrystal structures
UMass Chan Affiliations
Schiffer LabGraduate School of Biomedical Sciences
Department of Biochemistry and Molecular Pharmacology
Document Type
Journal ArticlePublication Date
2020-03-01Keywords
HIV-1 proteasehomo-oligomers
homodimers
merohedral twinning
twin law
Amino Acids, Peptides, and Proteins
Biochemistry
Enzymes and Coenzymes
Medicinal-Pharmaceutical Chemistry
Pharmaceutics and Drug Design
Structural Biology
Viruses
Metadata
Show full item recordAbstract
Twinning is a crystal-growth anomaly in which protein monomers exist in different orientations but are related in a specific way, causing diffraction reflections to overlap. Twinning imposes additional symmetry on the data, often leading to the assignment of a higher symmetry space group. Specifically, in merohedral twinning, reflections from each monomer overlap and require a twin law to model unique structural data from overlapping reflections. Neglecting twinning in the crystallographic analysis of quasi-rotationally symmetric homo-oligomeric protein structures can mask the degree of structural non-identity between monomers. In particular, any deviations from perfect symmetry will be lost if higher than appropriate symmetry is applied during crystallographic analysis. Such cases warrant choosing between the highest symmetry space group possible or determining whether the monomers have distinguishable structural asymmetries and thus require a lower symmetry space group and a twin law. Using hexagonal cocrystals of HIV-1 protease, a C2-symmetric homodimer whose symmetry is broken by bound ligand, it is shown that both assigning a lower symmetry space group and applying a twin law during refinement are critical to achieving a structural model that more accurately fits the electron density. By re-analyzing three recently published HIV-1 protease structures, improvements in nearly every crystallographic metric are demonstrated. Most importantly, a procedure is demonstrated where the inhibitor can be reliably modeled in a single orientation. This protocol may be applicable to many other homo-oligomers in the PDB.Source
Lockbaum GJ, Leidner F, Royer WE, Kurt Yilmaz N, Schiffer CA. Optimizing the refinement of merohedrally twinned P61 HIV-1 protease-inhibitor cocrystal structures. Acta Crystallogr D Struct Biol. 2020 Mar 1;76(Pt 3):302-310. doi: 10.1107/S2059798320001989. Epub 2020 Mar 2. PMID: 32133994; PMCID: PMC7057220. Link to article on publisher's site
DOI
10.1107/S2059798320001989Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29437PubMed ID
32133994Related Resources
ae974a485f413a2113503eed53cd6c53
10.1107/S2059798320001989