Binding site of AChR: Difference between revisions

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Acetylcholine receptor is a member of pentameric ligand gated ion channels family,which share the similar structure. Pentameric ligand gated ion channels (pLGIC), or [http://en.wikipedia.org/wiki/Cys-loop_receptors Cys-loop receptors],are a group of transmembrane ion channel proteins which open to allow ions such as Na+, K+, Ca2+, or Cl- to pass through the membrane in response to the binding of a chemical messenger, such as a neurotransmitter<ref> Purves, Dale, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, and Leonard E. White (2008). Neuroscience. 4th ed. Sinauer Associates. pp. 156–7. ISBN 978-0-87893-697-7.</ref>. In overall organization, the <scene name='68/688431/Plgics/1'>pLGICs</scene> have five subunits. The five subunits are arranged in a barrel-like manner around a central symmetry axis that coincides with the ion permeation pathway.<ref>PMID:24167270</ref> In each subunit, the extracellular domin(ECD) of pLGIC encompasses 10β-strands that are organized as a sandwich of two tightly interacting β-sheets, while the transmembrane domain(TMD) folds into a bundle of four α-helices (M1, M2, M3, M4).

[[Image:M2 helices.PNG|thumb|350px|Fig. 2. Top view of GLIC M2 helices|left]]

[[Image:Mechanism of GLIC.PNG|thumb|350px|Fig. 3. Open GLIC and closed ELIC structure comarison green is GLIC and red is ELIC]]

X-ray structure of homologues of the extracellular domain(ECD) of nAChRs have also been described:the acetylcholine binding protein(AChBP) co-crystallized with agonists and antagonists, and the ECD of α1-nAChRs. Most pLGICs undergo desensitization on prolonged exposure to agonist, complicating structural investigations of the transient open conformation. <ref>PMID:18987633</ref> The overall architecture of bacterial Gloeobacter violaceus pentameric ligand-gated ion(GLIC) is similar to nAChR(Fig 1). The five subunits are arranged in a barrel-like manner around a central symmetry axis that coincides with the ion permeation pathway.<ref>PMID:18987633</ref> The transmembrane domain of each subunit consists of four helices and M2 helices form the wall of the pore(Fig 2).Figure 2 shows that helix backbones and side chains facing the pore are depicted. Hydrophobic, polar and negative residues are coloured yellow, green and red respectively. The M2 axes are tilted with respect to the pore axis, with outer hydrophobic side chain oriented toward the helix interfaces, and inner polar side chains oriented towards the pore.<ref>PMID:18987633</ref>

The mechanism of pLGIC: in the TMD, the outer ends of M2 and M3 of GLIC are tilted away radially from the channel axis, while the outer end of M1 is fixed. The inner ends of M1, M2 and M3 move tangentially towards the left, when viewed from the membrane (Fig. 3b). In the ECD, the core of the b-sandwich undergoes little deformation, but is rotated by 8u around an axis roughly perpendicular to the inner sheet of the β-sandwich (Fig. 3a), concomitant with a rearrangement of both the subunit–subunit and the ECD/TMD interfaces, regions known to contribute to neurotransmitter gating. The latter contains the well-conserved β6–β7 and M2–M3 loops and the b1–b2 loop whose length is conserved in the pLGIC family. We observe a downward motion of the β1–β2 loop, concomitant with a displacement of the M2–M3 loop, M2 and M3 helices and b6–b7 loop towards the periphery of the molecule (Fig. 3c), thereby opening the pore. Such twist to open motions, initially proposed from ab initio normal mode analysis of nAChRs, and observed for Kcsa, may plausibly be extended to eukaryotic pLGICs. The structural transition described here couples in an allosteric manner the opening–closing motion of the pore with distant binding sites—located at the ECD subunit interface for neurotransmitters, or within the TMD for allosteric effectors30—and may possibly serve as a general mechanism of signal transduction in pLGICs.<ref>PMID:18987633</ref>

The mechanism of pLGIC is provided by Prof. Jean-Pierre in the paper 'X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation'(Nature,2009): helices M1, M2 and M3, and a large portion of the β-sandwich consisting of strands b1, b2, b6, b7 and b10, these elements constitute the subunit ‘common core’. Common core superimposition shows that the GLIC subunits display a quaternary twist compared to ELIC, with anticlockwise (versus clockwise) rotation in the upper (versus lower) part of the pentamer, when viewed from the extracellular compartment (Fig. 3a). This is confirmed by normal mode analysis: the lowest frequency mode is precisely a twist mode and has by far the highest contribution (29%) to the transition. However, we note that the first 100 lowest-frequency modes (usually the most collective ones) only explain about 50% of the transition. Other and more local movements occur:in the TMD, the outer ends of M2 and M3 of GLIC are tilted away radially from the channel axis, while the outer end of M1 is fixed. The inner ends of M1, M2 and M3 move tangentially towards the left, when viewed from the membrane (Fig. 3b). In the ECD, the core of the b-sandwich undergoes little deformation, but is rotated by 8u around an axis roughly perpendicular to the inner sheet of the β-sandwich (Fig. 3a), concomitant with a rearrangement of both the subunit–subunit and the ECD/TMD interfaces, regions known to contribute to neurotransmitter gating. The latter contains the well-conserved β6–β7 and M2–M3 loops and the b1–b2 loop whose length is conserved in the pLGIC family. We observe a downward motion of the β1–β2 loop, concomitant with a displacement of the M2–M3 loop, M2 and M3 helices and b6–b7 loop towards the periphery of the molecule (Fig. 3c), thereby opening the pore. Such twist to open motions, initially proposed from ab initio normal mode analysis of nAChRs, and observed for Kcsa, may plausibly be extended to eukaryotic pLGICs. The structural transition described here couples in an allosteric manner the opening–closing motion of the pore with distant binding sites—located at the ECD subunit interface for neurotransmitters, or within the TMD for allosteric effectors30—and may possibly serve as a general mechanism of signal transduction in pLGICs.<ref>PMID:18987633</ref>

== Superimpose HAP on AChBP ==

Binding site of AChR: Difference between revisions

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 Acetylcholine receptor is a member of pentameric ligand gated ion channels family,which share the similar structure. Pentameric ligand gated ion channels (pLGIC), or [http://en.wikipedia.org/wiki/Cys-loop_receptors Cys-loop receptors],are a group of transmembrane ion channel proteins which open to allow ions such as Na+, K+, Ca2+, or Cl- to pass through the membrane in response to the binding of a chemical messenger, such as a neurotransmitter<ref> Purves, Dale, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, and Leonard E. White (2008). Neuroscience. 4th ed. Sinauer Associates. pp. 156–7. ISBN 978-0-87893-697-7.</ref>. In overall organization, the <scene name='68/688431/Plgics/1'>pLGICs</scene> have five subunits. The five subunits are arranged in a barrel-like manner around a central symmetry axis that coincides with the ion permeation pathway.<ref>PMID:24167270</ref> In each subunit, the extracellular domin(ECD) of pLGIC encompasses 10β-strands that are organized as a sandwich of two tightly interacting β-sheets, while the transmembrane domain(TMD) folds into a bundle of four α-helices (M1, M2, M3, M4).
 [[Image:M2 helices.PNG|thumb|350px|Fig. 2. Top view of GLIC M2 helices|left]]
 [[Image:Mechanism of GLIC.PNG|thumb|350px|Fig. 3. Open GLIC and closed ELIC structure comarison green is GLIC and red is ELIC]]
 X-ray structure of homologues of the extracellular domain(ECD) of nAChRs have also been described:the acetylcholine binding protein(AChBP) co-crystallized with agonists and antagonists, and the ECD of α1-nAChRs. Most pLGICs undergo desensitization on prolonged exposure to agonist, complicating structural investigations of the transient open conformation. <ref>PMID:18987633</ref> The overall architecture of bacterial Gloeobacter violaceus pentameric ligand-gated ion(GLIC) is similar to nAChR(Fig 1). The five subunits are arranged in a barrel-like manner around a central symmetry axis that coincides with the ion permeation pathway.<ref>PMID:18987633</ref> The transmembrane domain of each subunit consists of four helices and M2 helices form the wall of the pore(Fig 2).Figure 2 shows that helix backbones and side chains facing the pore are depicted. Hydrophobic, polar and negative residues are coloured yellow, green and red respectively. The M2 axes are tilted with respect to the pore axis, with outer hydrophobic side chain oriented toward the helix interfaces, and inner polar side chains oriented towards the pore.<ref>PMID:18987633</ref>
-The mechanism of pLGIC: in the TMD, the outer ends of M2 and M3 of GLIC are tilted away radially from the channel axis, while the outer end of M1 is fixed. The inner ends of M1, M2 and M3 move tangentially towards the left, when viewed from the membrane (Fig. 3b). In the ECD, the core of the b-sandwich undergoes little deformation, but is rotated by 8u around an axis roughly perpendicular to the inner sheet of the β-sandwich (Fig. 3a), concomitant with a rearrangement of both the subunit–subunit and the ECD/TMD interfaces, regions known to contribute to neurotransmitter gating. The latter contains the well-conserved β6–β7 and M2–M3 loops and the b1–b2 loop whose length is conserved in the pLGIC family. We observe a downward motion of the β1–β2 loop, concomitant with a displacement of the M2–M3 loop, M2 and M3 helices and b6–b7 loop towards the periphery of the molecule (Fig. 3c), thereby opening the pore. Such twist to open motions, initially proposed from ab initio normal mode analysis of nAChRs, and observed for Kcsa, may plausibly be extended to eukaryotic pLGICs. The structural transition described here couples in an allosteric manner the opening–closing motion of the pore with distant binding sites—located at the ECD subunit interface for neurotransmitters, or within the TMD for allosteric effectors30—and may possibly serve as a general mechanism of signal transduction in pLGICs.<ref>PMID:18987633</ref>
+The mechanism of pLGIC is provided by Prof. Jean-Pierre in the paper 'X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation'(Nature,2009): helices M1, M2 and M3, and a large portion of the β-sandwich consisting of strands b1, b2, b6, b7 and b10, these elements constitute the subunit ‘common core’. Common core superimposition shows that the GLIC subunits display a quaternary twist compared to ELIC, with anticlockwise (versus clockwise) rotation in the upper (versus lower) part of the pentamer, when viewed from the extracellular compartment (Fig. 3a). This is confirmed by normal mode analysis: the lowest frequency mode is precisely a twist mode and has by far the highest contribution (29%) to the transition. However, we note that the first 100 lowest-frequency modes (usually the most collective ones) only explain about 50% of the transition. Other and more local movements occur:in the TMD, the outer ends of M2 and M3 of GLIC are tilted away radially from the channel axis, while the outer end of M1 is fixed. The inner ends of M1, M2 and M3 move tangentially towards the left, when viewed from the membrane (Fig. 3b). In the ECD, the core of the b-sandwich undergoes little deformation, but is rotated by 8u around an axis roughly perpendicular to the inner sheet of the β-sandwich (Fig. 3a), concomitant with a rearrangement of both the subunit–subunit and the ECD/TMD interfaces, regions known to contribute to neurotransmitter gating. The latter contains the well-conserved β6–β7 and M2–M3 loops and the b1–b2 loop whose length is conserved in the pLGIC family. We observe a downward motion of the β1–β2 loop, concomitant with a displacement of the M2–M3 loop, M2 and M3 helices and b6–b7 loop towards the periphery of the molecule (Fig. 3c), thereby opening the pore. Such twist to open motions, initially proposed from ab initio normal mode analysis of nAChRs, and observed for Kcsa, may plausibly be extended to eukaryotic pLGICs. The structural transition described here couples in an allosteric manner the opening–closing motion of the pore with distant binding sites—located at the ECD subunit interface for neurotransmitters, or within the TMD for allosteric effectors30—and may possibly serve as a general mechanism of signal transduction in pLGICs.<ref>PMID:18987633</ref>
 == Superimpose HAP on AChBP ==