Hot Topics: Structural Basis of Substrate Recognition by the Multidrug Resistance Protein MRP1

Despite a flurry of mammalian ATP binding cassette (ABC) transporter structures in the last 2 years the Holy Grail has still been to determine how these diverse proteins interact with their transport substrates. Jue Chen and colleagues at the Rockefeller have now accomplished this for  the multidrug resistance protein-1 (MRP1/ABCC1) using advances in high resolution cryo-electron microscopy to show the structures of substrate-free and leukotriene C4 bound protein [1]. The paper also lays the foundation for revealing the structural basis for multidrug transport by MRP1 (which is a confounding factor for some chemotherapies) as the flexible substrate binding cavity in the membrane has both polar and a hydrophobic sub-pockets enabling it to interact with chemically diverse drugs. Whether this structural data enables the design of clinically-relevant MRP1 inhibitors will now be the focus of much research.

[1] Johnson Z.L., Chen J. (2017). Structural Basis of Substrate Recognition by the Multidrug Resistance Protein MRP1. Cell. pii: S0092-8674(17)30131-9. [PMID: 28238471]

Comments by Prof. Ian Kerr, University of Nottingham (@iankerr_science)

http://www.nottingham.ac.uk/life-sciences/people/ian.kerr

https://www.linkedin.com/in/ian-kerr-2b94742b/

Posted in Hot Topics

Hot Topics: The complete structure of an activated open sodium channel

Voltage-gated sodium channels (Navs) play essential roles in excitable tissues, with their activation and opening resulting in the initial phase of the action potential. The cycling of Navs through open, closed and inactivated states, and their closely choreographed relationships with the activities of other ion channels lead to exquisite control of intracellular ion concentrations in both prokaryotes and eukaryotes. Here we present the 2.45 Å resolution crystal structure of the complete NavMs prokaryotic sodium channel in a fully open conformation. A canonical activated conformation of the voltage sensor S4 helix, an open selectivity filter leading to an open activation gate at the intracellular membrane surface and the intracellular C-terminal domain are visible in the structure. It includes a heretofore unseen interaction motif between W77 of S3, the S4–S5 interdomain linker, and the C-terminus, which is associated with regulation of opening and closing of the intracellular gate.

[1] Sula et al. (2016). The complete structure of an activated open sodium channel. Nat. Commun. 16;8:14205. [PMID: 28205548]

Comments by Curation Team

Posted in Hot Topics

Hot topics: Peripherally administered orexin improves survival of mice with endotoxin shock

Sepsis is a systemic inflammatory response to infection, accounting for the most common cause of death in intensive care units. Here, we report that peripheral administration of the hypothalamic neuropeptide orexin improves the survival of mice with lipopolysaccharide (LPS) induced endotoxin shock, a well-studied septic shock model.

oxerin-A (GtoPdb ligand ID: 1697)

oxerin-B (GtoPdb ligand ID: 1699)

[1] Ogawa et al. (2017). Elife 5:e21055. Peripherally administered orexin improves survival of mice with endotoxin shock. [PMID: 28035899]

Comments by Curation Team

Posted in Hot Topics

Hot topics: Targeted Elimination of G Proteins and Arrestins Defines Their Specific Contributions to Both Intensity and Duration of G Protein-coupled Receptor Signaling

This study employs CRISPR/Cas9 genome editing to eliminate selected G proteins (Gαq and Gα11) or arrestin2 and arrestin3 from HEK293 cells together with the elimination of receptor phosphorylation sites to define the relative contribution of G proteins, arrestins, and receptor phosphorylation to the signaling outcomes of the free fatty acid receptor 4 (FFA4). The authors validate CRISPR/Cas9 engineered HEK293 cells lacking Gq/11 or arrestin2/3 as systems for GPCR signaling research and employ these cells to reveal a previously unappreciated interplay of signaling pathways where receptor phosphorylation can impact on ERK1/2 signaling through a mechanism that is likely independent of arrestins.

[1] Alvarez-Curto et al. (2017). J. Biol. Chem. 291(53):27147-27159. Targeted Elimination of G Proteins and Arrestins Defines Their Specific Contributions to Both Intensity and Duration of G Protein-coupled Receptor Signaling. [PMID: 27852822]

Comments by Curation Team.

Posted in Hot Topics

Hot topics: Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin

A report on the discovery of a new potent allosteric effector of sickle cell haemoglobin, GBT440, that increases the affinity of haemoglobin for oxygen and consequently inhibits its polymerisation when subjected to hypoxic conditions. GBT440 is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813).

[1] Metcalf et al. (2017). ACS Medical Chemistry Letters DOI:10.1021/acsmedchemlett.6b00491. Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. [link]

Comments by Curation Team

Posted in Hot Topics

Hot topics: Crystal Structure of an LSD-Bound Human Serotonin Receptor

The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT2B. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD’s actions at human serotonin receptors.

[1] Wacker et al. (2017). Cell 168(3):377-389. Crystal Structure of an LSD-Bound Human Serotonin Receptor. [PMID: 28129538]

Comments by Curation Team

Posted in Hot Topics

Hot topics: Structures of the Human HCN1 Hyperpolarization-Activated Channel

Presenting cryo-electron microscopy structures of the human HCN channel in the absence and presence of cAMP at 3.5 Å resolution. HCN channels contain a K+channel selectivity filter-forming sequence from which the amino acids create a unique structure that explains Na+ and K+ permeability. These structures advance understanding of ion selectivity, reversed polarity gating, and cAMP regulation in HCN channels

[1] Lee C.H. & MacKinnon R. (2017). Cell 168(1-2):111-120. Structures of the Human HCN1 Hyperpolarization-Activated Channel. [PMID: 28086084].

Comments by Curation Team

Posted in Hot Topics