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Assays for screening compounds which interact with cation channel proteins, mutant prokaryotic cation channel proteins, and uses thereof

a technology crystal structure, which is applied in the field of crystal structure of cation channel protein, can solve the problems of difficult to isolate and purify potassium channel protein, few drugs or therapeutic agents that act on potassium channel protein to treat abnormal processes, and low availability of isolated potassium channel protein in abundan

Inactive Publication Date: 2005-12-08
MACKINNON RODERICK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This method enables efficient screening of potential drugs or agents for interaction with cation channel proteins, overcoming the limitations of protein isolation and purification, and identifying candidates for treating conditions like cardiac arrhythmia, diabetes mellitus, and hypertension.

Problems solved by technology

Although potassium channel proteins are involved in such a wide variety of homeostatic functions, few drugs or therapeutic agents are available that act on potassium channel proteins to treat abnormal processes.
A reason for a lack of presently available drugs that act on potassium channel proteins is that isolated potassium channel proteins are not available in great abundance, mainly because an animal cell requires only a very limited number of such channel proteins in order to function.
Consequently, it has been very difficult to isolate and purify potassium channel proteins, reducing the amount of drug screening efforts in search of potassium channel protein acting drugs.

Method used

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  • Assays for screening compounds which interact with cation channel proteins, mutant prokaryotic cation channel proteins, and uses thereof
  • Assays for screening compounds which interact with cation channel proteins, mutant prokaryotic cation channel proteins, and uses thereof
  • Assays for screening compounds which interact with cation channel proteins, mutant prokaryotic cation channel proteins, and uses thereof

Examples

Experimental program
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example i

Potassium Channel Structure: Molecular Basis of K+ Conduction and Selectivity

[0475] The K+ channel from Streptomyces lividans is an integral membrane protein with sequence similarity to all known K+ channels, particularly in the pore region. X-ray analysis with data to 3.2 (reveals that four identical subunits create an inverted tepee, or cone, cradling the selectivity filter of the pore in its outer end. The narrow selectivity filter is only 12 Å long, while the remainder of the pore is wider and lined with hydrophobic amino acids. A large, water-filled cavity and helix dipoles are positioned so as to overcome electrostatic destabilization of an ion in the pore at the center of the bilayer. Main-chain carbonyl oxygen atoms from the K+ channel signature sequence line the selectivity filter, which is held open by structural constraints to coordinate K+ ions but not smaller Na+ ions. The selectivity filter contains two K+ ions about 7.5 Å apart. This configuration promotes ion condu...

example ii

Structural Conservation in Prokaryotic and Eukaryotic K− Channels Revealed by Scorpion Toxins

[0521] Scorpion toxins inhibit ion conduction through K+ channels by occluding the pore at their extracellular opening. A single toxin protein binds very specifically to a single K+ channel to cause inhibition. The toxins are 35 to 40 amino acids in length and have a characteristic fold that is held rigidly by three disulfide bridges (1). They are active site inhibitors, because when they bind to the channel they interact energetically with K+ ions in the pore (2-4). The intimate interaction between these inhibitors and the pore of K+ channels has been exploited to gain insights into the structure and function of K+ channels.

[0522] Studies employing site-directed mutagenesis of the Shaker K+ channel have mapped the scorpion toxin binding site to regions corresponding to the extracellular entryway of the kcsa K+ channel (4-9). Although the K+ channel selectivity filter amino acids are highl...

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Abstract

Assays for screeing potential drugs or agents that can interact and potentially bind to cation channel proteins, and potentially have uses in treating conditions related to the function of cation channel proteins is provided, along with prokaryotic cation channel proteins mutated to mimic eukaryotic cation channels, which can then be used in assays of the present invention.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation in part of copending U.S. application Ser. No. 09 / 054,347 filed on Apr. 2, 1998, which is a continuation in part of copending U.S. application Ser. No. 09 / 045,529 filed on Mar. 20, 1998, wherein both U.S. Ser. Nos. 09 / 054,347 and 09 / 045,529 are hereby incorporated by reference in their entireties.GOVERNMENT RIGHTS CLAUSE [0002] The research leading to the present invention was supported in part with National Institutes of Health Grant GM 43949. The government may have rights in the invention.FIELD OF INVENTION [0003] The present invention relates to a crystal of a cation channel protein, and methods of using such a crystal in screening potential drugs and therapeutic agents for use in treating conditions related to the function of such channels in vivo. BACKGROUND OF INVENTION [0004] Although numerous types of channel proteins are known, the main types of ion channel proteins are characterized by the m...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07H21/04C12P21/02C07K14/435C07K14/195G01N33/68C07K14/36G01N33/94G01N33/53C07K14/705C12N1/21
CPCC07K14/195C07K14/36C07K14/43581C07K14/705G01N33/6872G01N33/94G01N2500/00
Inventor MACKINNON, RODERICK
Owner MACKINNON RODERICK
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