Protein–phospholipid interplay revealed with crystals of a calcium pump

Norimatsu, Yoshiyuki; Hasegawa, Kazuya; Shimizu, Nobutaka; Toyoshima, Chikashi

doi:10.1038/nature22357

Cited by 129 publications

(148 citation statements)

References 47 publications

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“…S8 B ). Those positively charged residues may interact with the negatively charged phospholipid head groups of the membrane bilayers (55). The surface of the catalytic domain is a mix of positive and negative patches, but it is clear that the exposed active site is negatively charged and lies on the large interface between the catalytic and TM domains.…”

Section: Resultsmentioning

confidence: 99%

Substrate analog interaction with MCR‐1 offers insight into the rising threat of the plasmid‐mediated transferable colistin resistance

et al. 2018

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Colistin is considered a last-resort antibiotic against most gram-negative bacteria. Recent discoveries of a plasmid-mediated, transferable mobilized colistin-resistance gene ( mcr-1) on all continents have heralded the imminent emergence of pan-drug-resistant superbacteria. The inner-membrane protein MCR-1 can catalyze the transfer of phosphoethanolamine (PEA) to lipid A, resulting in colistin resistance. However, little is known about the mechanism, and few drugs exist to address this issue. We present crystal structures revealing the MCR-1 catalytic domain (cMCR-1) as a monozinc metalloprotein with ethanolamine (ETA) and d-glucose, respectively, thus highlighting 2 possible substrate-binding pockets in the MCR-1-catalyzed PEA transfer reaction. Mutation of the residues involved in ETA and d-glucose binding impairs colistin resistance in recombinant Escherichia coli containing full-length MCR-1. Partial analogs of the substrate are used for cocrystallization with cMCR-1, providing valuable information about the family of PEA transferases. One of the analogs, ETA, causes clear inhibition of polymyxin B resistance, highlighting its potential for drug development. These data demonstrate the crucial role of the PEA- and lipid A-binding pockets and provide novel insights into the structure-based mechanisms, important drug-target hot spots, and a drug template for further drug development to combat the urgent, rising threat of MCR-1-mediated antibiotic resistance.-Wei, P., Song, G., Shi, M., Zhou, Y., Liu, Y., Lei, J., Chen, P., Yin, L. Substrate analog interaction with MCR-1 offers insight into the rising threat of the plasmid-mediated transferable colistin resistance.

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Section: Resultsmentioning

confidence: 99%

Substrate analog interaction with MCR‐1 offers insight into the rising threat of the plasmid‐mediated transferable colistin resistance

et al. 2018

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“…In the preceding work (12), the entire first layer of phospholipids surrounding the transmembrane helices of SERCA1a was visualized in the electron density maps obtained by X-ray solvent contrast modulation. By superimposing the present cryo-EM structures of SERCA2b to the crystal structures of SERCA1a with the surrounding phospholipids, we found that the LE runs parallel to the lipid-water boundary in the luminal side ( Fig. 2C &D).…”

Section: Overall Structures Of Serca2b In E1•2ca 2+ -Amppcp and E2-bementioning

confidence: 99%

Cryo-EM structures of SERCA2b reveal the mechanism of regulation by the luminal extension tail

Zhang

Inoue

Tsutsumi

et al. 2020

Preprint

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One sentence summary:Cryo-EM structures of SERCA2b at 2.8-2.9 Å resolutions reveal how the luminal extension tail regulates its activity. AbstractSERCA2b is a Ca 2+ -ATPase that pumps Ca 2+ from the cytosol into the ER and maintains the cellular calcium homeostasis. Herein, we present cryo-EM structures of human SERCA2b in E1•2Ca 2+ -AMPPCP and E2-BeF3states at 2.9 and 2.8 Å resolutions, respectively. The structures revealed that the luminal extension tail (LE) characteristic of SERCA2b runs parallel to the lipid-water boundary near the luminal ends of transmembrane (TM) helices TM10 and TM7, and approaches the luminal loop flanked by TM7 and TM8. Upon deletion of the LE, the cytosolic-and TM-domain arrangement of SERCA2b resembled that of SERCA1a, resulting in multiple conformations. The LE regulates the conformational transition between the E1•2Ca 2+ -ATP and E2P states, explaining the different kinetic properties of SERCA2b from other isoforms lacking the LE.

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“…Setting an occupancy threshold of 10% resulted in a ring-shaped surface around the TM domain while increasing this value to 50% displayed very circumscribed regions in the surroundings of Lys262 and Arg63 basic moieties, both previously reported as residues implicated in snorkeling interactions. 86…”

Section: Case Study 4: Sarcoendoplasmic Reticulum Calcium Atpase (Sermentioning

confidence: 99%

Fat SIRAH: Coarse-grained phospholipids to explore membrane-protein dynamics

Barrera

Machado

Pantano

2019

Preprint

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The capability to handle highly heterogeneous molecular assemblies in a consistent manner is among the greatest challenges faced when deriving simulation parameters. This is particularly the case for coarse-grained simulations in which chemical functional groups are lumped into effective interaction centers for which transferability between different chemical environments is not guaranteed. Here we introduce the parameterization of a set of CG phospholipids compatible with the latest version of the SIRAH force field for proteins. The newly introduced lipid species include different acylic chain lengths, partial unsaturation, as well as polar and acidic head groups that show a very good reproduction of structural membrane determinants, as areas per lipid, thickness, order parameter, etc., and their dependence with temperature. Simulation of membrane proteins showed unprecedented accuracy in the unbiased description of the thickness-dependent membrane-protein orientation in systems where this information is experimentally available (namely, the SarcoEndoplasmic Reticulum Calcium -SERCA-pump and its regulator Phospholamban). The interactions that lead to this faithful reproduction can be traced down to single amino acid-lipid interaction level and show full agreement with biochemical data present in the literature. Finally, the present parameterization is implemented in the GROMACS and AMBER simulation packages facilitating its use to a wide portion of the Biocomputing community.

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Protein–phospholipid interplay revealed with crystals of a calcium pump

Cited by 129 publications

References 47 publications

Substrate analog interaction with MCR‐1 offers insight into the rising threat of the plasmid‐mediated transferable colistin resistance

Substrate analog interaction with MCR‐1 offers insight into the rising threat of the plasmid‐mediated transferable colistin resistance

Cryo-EM structures of SERCA2b reveal the mechanism of regulation by the luminal extension tail

Fat SIRAH: Coarse-grained phospholipids to explore membrane-protein dynamics

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