Structure, Thermodynamics, and Kinetics of Plinabulin Binding to Two Tubulin Isotypes

Sala, Giuseppina La; Olieric, Natacha; Sharma, Ashwani; Viti, Federica; Perez, Francisco de Asis Balaguer; Huang, Lan; Tonra, James R.; Lloyd, G. Kenneth; Decherchi, Sergio; Dı́az, José Fernando; Steinmetz, Michel O.; Cavalli, Andrea

doi:10.1016/j.chempr.2019.08.022

Cited by 41 publications

(50 citation statements)

References 67 publications

(71 reference statements)

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“…The intermediate domain movement could be characterized as a rotation of its b sheet and a translation of the H7 helix. Essentially the same conclusion can be derived from the comparison of the higher resolution data that are now available, reaching 3.1 Å in the case of the microtubule (pdb id 6DPU; Zhang et al, 2018) and 1.52 Å in that of a tubulin-DARPin complex (pdb id 6S8K; La Sala et al, 2019). Interestingly, although the H7 helix is part of the intermediate domain, the adjacent H6 and H8 helices hardly belong to any of the two domains.…”

Section: The Tubulin Conformational Changes Associated With Microtubule Assemblysupporting

confidence: 64%

The Mechanism of Tubulin Assembly into Microtubules: Insights from Structural Studies

et al. 2020

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Summary Microtubules are cytoskeletal components involved in pivotal eukaryotic functions such as cell division, ciliogenesis, and intracellular trafficking. They assemble from αβ-tubulin heterodimers and disassemble in a process called dynamic instability, which is driven by GTP hydrolysis. Structures of the microtubule and of soluble tubulin have been determined by cryo-EM and by X-ray crystallography, respectively. Altogether, these data define the mechanism of tubulin assembly-disassembly at atomic or near-atomic level. We review here the structural changes that occur during assembly, tubulin switching from a curved conformation in solution to a straight one in the microtubule core. We also present more subtle changes associated with GTP binding, leading to tubulin activation for assembly. Finally, we show how cryo-EM and X-ray crystallography are complementary methods to characterize the interaction of tubulin with proteins involved either in intracellular transport or in microtubule dynamics regulation.

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Section: The Tubulin Conformational Changes Associated With Microtubule Assemblysupporting

confidence: 64%

The Mechanism of Tubulin Assembly into Microtubules: Insights from Structural Studies

et al. 2020

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“…Support for this mechanism can be found in the structures of eukaryotic tubulins. A water molecule is found bound to a-tubulin Glu254 in the sequestered a/b-tubulin dimer (21), equivalent to the hydrolytic water bound to Glu251 in OdinTubulin (compare Fig. 4B and 4C).…”

Section: Conservation With Microtubule-forming Tubulinsmentioning

confidence: 91%

Structure and dynamics of Odinarchaeota tubulin and the implications for eukaryotic microtubule evolution

Akıl

Ali

Tran

et al. 2021

Preprint

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Tubulins are critical for the internal organization of eukaryotic cells, and understanding their emergence is an important question in eukaryogenesis. Asgard archaea are the closest known prokaryotic relatives to eukaryotes. Here, we elucidated the apo and nucleotide-bound X-ray structures of an Asgard tubulin from hydrothermal-living Odinarchaeota (OdinTubulin). The GTP-bound structure resembles a microtubule protofilament, with GTP bound between subunits, coordinating the + end subunit through a network of water molecules and unexpectedly by two cations. A water molecule is located suitable for GTP hydrolysis. Time course crystallography and electron microscopy revealed conformational changes on GTP hydrolysis. OdinTubulin forms tubules at high temperatures, with short curved protofilaments coiling around the tubule circumference, more similar to FtsZ, rather than running parallel to its length, as in microtubules. Thus, OdinTubulin represents an evolution intermediate between prokaryotic FtsZ and eukaryotic microtubule-forming tubulins.

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“…Importantly, plinabulin significantly reduced CIN in cancer patients when administered within 1 h following treatment with another tubulintargeted therapy, docetaxel (Taxotere ® ) [9] [Mohanlal et al, ASCO-SITC 2018, Abstract 126]. This effect stands in contrast to the worsening of CIN by combretastatin A4 [14], a small molecule that also binds to the colchicine pocket, but at a site and with kinetics that differ from that of plinabulin [15]. Studies reported here aimed to determine whether plinabulin could act as a broad acting anti-CIN agent with multiple chemotherapies of diverse classes, utilizing a mechanism distinct from approved therapies that increase circulating G-CSF.…”

Section: Introductionmentioning

confidence: 99%

Plinabulin ameliorates neutropenia induced by multiple chemotherapies through a mechanism distinct from G-CSF therapies

Tonra¹,

Lloyd²,

Mohanlal³

et al. 2019

Cancer Chemother Pharmacol

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Purpose Chemotherapy-induced neutropenia (CIN) increases the risk of infections and mortality in cancer patients. G-CSF therapies are approved for the treatment of CIN, but non-G-CSF therapies are needed to increase efficacy and minimize side effects. Plinabulin is an inhibitor of tubulin polymerization that ameliorates CIN caused in patients by the microtubule stabilizer docetaxel. The present study evaluates the potential of plinabulin to reduce neutropenia induced by chemotherapies of different classes in a manner not dependent on increasing G-CSF. Methods The anti-CIN benefits of plinabulin were tested in rodents co-treated with docetaxel, cyclophosphamide or doxorubicin. Effects on G-CSF levels were evaluated in tissues by immunoassay. Flow cytometry was utilized to test treatment effects on femur bone marrow cell counts from immunocompetent mice-bearing orthotopic 4T1 breast cancer tumors. Results Plinabulin alleviated neutropenia induced by microtubule stabilizing, DNA cross-linking and DNA intercalating chemotherapies, yet did not affect bone marrow or blood G-CSF levels. The number of lineage − /Sca1 + /c-Kit + (LSK) hematopoietic stem/progenitor cells (HSPC) in murine bone marrow collected 2 days after treatment was not affected by docetaxel monotherapy despite increased plasma G-CSF in this group. LSK cell number was, however, increased when plinabulin was combined with docetaxel, without affecting G-CSF. Conclusions Results support the clinical testing of plinabulin as a non-G-CSF-based treatment for CIN associated with chemotherapies of different mechanisms. Results also support HSPC as a focal point for future mechanism-of-action work aimed at understanding the ability of plinabulin to reduce this serious side effect of cytotoxic therapy in cancer patients.

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Structure, Thermodynamics, and Kinetics of Plinabulin Binding to Two Tubulin Isotypes

Cited by 41 publications

References 67 publications

The Mechanism of Tubulin Assembly into Microtubules: Insights from Structural Studies

The Mechanism of Tubulin Assembly into Microtubules: Insights from Structural Studies

Structure and dynamics of Odinarchaeota tubulin and the implications for eukaryotic microtubule evolution

Plinabulin ameliorates neutropenia induced by multiple chemotherapies through a mechanism distinct from G-CSF therapies

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