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Paul A Mould - One of the best experts on this subject based on the ideXlab platform.

  • distinct roles of β1 metal ion dependent adhesion site midas adjacent to midas admidas and ligand associated metal binding site limbs cation binding sites in ligand recognition by integrin α2β1
    Journal of Biological Chemistry, 2008
    Co-Authors: Dimitra Valdramidou, Martin J Humphries, Paul A Mould
    Abstract:

    Abstract Integrin-ligand interactions are regulated in a complex manner by divalent cations, and previous studies have identified ligand-competent, stimulatory, and inhibitory cation-binding sites. In collagen-binding integrins, such as α2β1, ligand recognition takes place exclusively at the α subunit I domain. However, activation of the αI domain depends on its interaction with a structurally similar domain in the β subunit known as the I-like or βI domain. The top face of the βI domain contains three cation-binding sites: the metal-ion dependent adhesion site (MIDAS), the ADMIDAS (adjacent to MIDAS), and LIMBS (ligand-associated metal-binding site). The role of these sites in controlling ligand binding to the αI domain has yet to be elucidated. Mutation of the MIDAS or LIMBS completely blocked collagen binding to α2β1; in contrast mutation of the ADMIDAS reduced ligand recognition but this effect could be overcome by the activating monoclonal antibody TS2/16. Hence, the MIDAS and LIMBS appear to be essential for the interaction between αI and βI, whereas occupancy of the ADMIDAS has an allosteric effect on the conformation of βI. An activating mutation in the α2 I domain partially restored ligand binding to the MIDAS and LIMBS mutants. Analysis of the effects of Ca2+, Mg2+, and Mn2+ on ligand binding to these mutants showed that the MIDAS is a ligand-competent site through which Mn2+ stimulates ligand binding, whereas the LIMBS is a stimulatory Ca2+-binding site, occupancy of which increases the affinity of Mg2+ for the MIDAS.

  • distinct roles of β1 metal ion dependent adhesion site midas adjacent to midas admidas and ligand associated metal binding site limbs cation binding sites in ligand recognition by integrin α2β1
    Journal of Biological Chemistry, 2008
    Co-Authors: Dimitra Valdramidou, Martin J Humphries, Paul A Mould
    Abstract:

    Integrin-ligand interactions are regulated in a complex manner by divalent cations, and previous studies have identified ligand-competent, stimulatory, and inhibitory cation-binding sites. In collagen-binding integrins, such as alpha2beta1, ligand recognition takes place exclusively at the alpha subunit I domain. However, activation of the alphaI domain depends on its interaction with a structurally similar domain in the beta subunit known as the I-like or betaI domain. The top face of the betaI domain contains three cation-binding sites: the metal-ion dependent adhesion site (MIDAS), the ADMIDAS (adjacent to MIDAS), and LIMBS (ligand-associated metal-binding site). The role of these sites in controlling ligand binding to the alphaI domain has yet to be elucidated. Mutation of the MIDAS or LIMBS completely blocked collagen binding to alpha2beta1; in contrast mutation of the ADMIDAS reduced ligand recognition but this effect could be overcome by the activating monoclonal antibody TS2/16. Hence, the MIDAS and LIMBS appear to be essential for the interaction between alphaI and betaI, whereas occupancy of the ADMIDAS has an allosteric effect on the conformation of betaI. An activating mutation in the alpha2 I domain partially restored ligand binding to the MIDAS and LIMBS mutants. Analysis of the effects of Ca(2+), Mg(2+), and Mn(2+) on ligand binding to these mutants showed that the MIDAS is a ligand-competent site through which Mn(2+) stimulates ligand binding, whereas the LIMBS is a stimulatory Ca(2+)-binding site, occupancy of which increases the affinity of Mg(2+) for the MIDAS.

Amin M Arnaout - One of the best experts on this subject based on the ideXlab platform.

  • stable coordination of the inhibitory ca2 ion at the metal ion dependent adhesion site in integrin cd11b cd18 by an antibody derived ligand aspartate implications for integrin regulation and structure based drug design
    Journal of Immunology, 2011
    Co-Authors: Bhuvaneshwari Mahalingam, Jian-ping Xiong, Kaouther Ajroud, Jose Luis Alonso, Saurabh Anand, Brian D Adair, Alberto L Horenstein, Fabio Malavasi, Amin M Arnaout
    Abstract:

    A central feature of integrin interaction with physiologic ligands is the monodentate binding of a ligand carboxylate to a Mg2+ ion hexacoordinated at the metal ion-dependent adhesion site (MIDAS) in the integrin A domain. This interaction stabilizes the A domain in the high-affinity state, which is distinguished from the default low-affinity state by tertiary changes in the domain that culminate in cell adhesion. Small molecule ligand-mimetic integrin antagonists act as partial agonists, eliciting similar activating conformational changes in the A domain, which has contributed to paradoxical adhesion and increased patient mortality in large clinical trials. As with other ligand-mimetic integrin antagonists, the function-blocking mAb 107 binds MIDAS of integrin CD11b/CD18 A domain (CD11bA), but in contrast, it favors the inhibitory Ca2+ ion over the Mg2+ ion at MIDAS. We determined the crystal structures of the Fab fragment of mAb 107 complexed to the low- and high-affinity states of CD11bA. Favored binding of the Ca2+ ion at MIDAS is caused by the unusual symmetric bidentate ligation of a Fab-derived ligand Asp to a heptacoordinated MIDAS Ca2+ ion. Binding of the Fab fragment of mAb 107 to CD11bA did not trigger the activating tertiary changes in the domain or in the full-length integrin. These data show that the denticity of the ligand Asp/Glu can modify the divalent cation selectivity at MIDAS and hence integrin function. Stabilizing the Ca2+ ion at MIDAS by bidentate ligation to a ligand Asp/Glu may provide one approach for designing pure integrin antagonists.

  • stable coordination of the inhibitory ca 2 ion at the metal ion dependent adhesion site in integrin cd11b cd18 by an antibody derived ligand aspartate implications for integrin regulation and structure based drug design
    Journal of Immunology, 2011
    Co-Authors: Bhuvaneshwari Mahalingam, Jian-ping Xiong, Kaouther Ajroud, Jose Luis Alonso, Saurabh Anand, Brian D Adair, Alberto L Horenstein, Fabio Malavasi, Amin M Arnaout
    Abstract:

    A central feature of integrin interaction with physiologic ligands is the monodentate binding of a ligand carboxylate to a Mg 2+ ion hexacoordinated at the metal ion-dependent adhesion site (MIDAS) in the integrin A domain. This interaction stabilizes the A domain in the high-affinity state, which is distinguished from the default low-affinity state by tertiary changes in the domain that culminate in cell adhesion. Small molecule ligand-mimetic integrin antagonists act as partial agonists, eliciting similar activating conformational changes in the A domain, which has contributed to paradoxical adhesion and increased patient mortality in large clinical trials. As with other ligand-mimetic integrin antagonists, the function-blocking mAb 107 binds MIDAS of integrin CD11b/CD18 A domain (CD11bA), but in contrast, it favors the inhibitory Ca 2+ ion over the Mg 2+ ion at MIDAS. We determined the crystal structures of the Fab fragment of mAb 107 complexed to the low- and high-affinity states of CD11bA. Favored binding of the Ca 2+ ion at MIDAS is caused by the unusual symmetric bidentate ligation of a Fab-derived ligand Asp to a heptacoordinated MIDAS Ca 2+ ion. Binding of the Fab fragment of mAb 107 to CD11bA did not trigger the activating tertiary changes in the domain or in the full-length integrin. These data show that the denticity of the ligand Asp/Glu can modify the divalent cation selectivity at MIDAS and hence integrin function. Stabilizing the Ca 2+ ion at MIDAS by bidentate ligation to a ligand Asp/Glu may provide one approach for designing pure integrin antagonists.

Dimitra Valdramidou - One of the best experts on this subject based on the ideXlab platform.

  • distinct roles of β1 metal ion dependent adhesion site midas adjacent to midas admidas and ligand associated metal binding site limbs cation binding sites in ligand recognition by integrin α2β1
    Journal of Biological Chemistry, 2008
    Co-Authors: Dimitra Valdramidou, Martin J Humphries, Paul A Mould
    Abstract:

    Abstract Integrin-ligand interactions are regulated in a complex manner by divalent cations, and previous studies have identified ligand-competent, stimulatory, and inhibitory cation-binding sites. In collagen-binding integrins, such as α2β1, ligand recognition takes place exclusively at the α subunit I domain. However, activation of the αI domain depends on its interaction with a structurally similar domain in the β subunit known as the I-like or βI domain. The top face of the βI domain contains three cation-binding sites: the metal-ion dependent adhesion site (MIDAS), the ADMIDAS (adjacent to MIDAS), and LIMBS (ligand-associated metal-binding site). The role of these sites in controlling ligand binding to the αI domain has yet to be elucidated. Mutation of the MIDAS or LIMBS completely blocked collagen binding to α2β1; in contrast mutation of the ADMIDAS reduced ligand recognition but this effect could be overcome by the activating monoclonal antibody TS2/16. Hence, the MIDAS and LIMBS appear to be essential for the interaction between αI and βI, whereas occupancy of the ADMIDAS has an allosteric effect on the conformation of βI. An activating mutation in the α2 I domain partially restored ligand binding to the MIDAS and LIMBS mutants. Analysis of the effects of Ca2+, Mg2+, and Mn2+ on ligand binding to these mutants showed that the MIDAS is a ligand-competent site through which Mn2+ stimulates ligand binding, whereas the LIMBS is a stimulatory Ca2+-binding site, occupancy of which increases the affinity of Mg2+ for the MIDAS.

  • distinct roles of β1 metal ion dependent adhesion site midas adjacent to midas admidas and ligand associated metal binding site limbs cation binding sites in ligand recognition by integrin α2β1
    Journal of Biological Chemistry, 2008
    Co-Authors: Dimitra Valdramidou, Martin J Humphries, Paul A Mould
    Abstract:

    Integrin-ligand interactions are regulated in a complex manner by divalent cations, and previous studies have identified ligand-competent, stimulatory, and inhibitory cation-binding sites. In collagen-binding integrins, such as alpha2beta1, ligand recognition takes place exclusively at the alpha subunit I domain. However, activation of the alphaI domain depends on its interaction with a structurally similar domain in the beta subunit known as the I-like or betaI domain. The top face of the betaI domain contains three cation-binding sites: the metal-ion dependent adhesion site (MIDAS), the ADMIDAS (adjacent to MIDAS), and LIMBS (ligand-associated metal-binding site). The role of these sites in controlling ligand binding to the alphaI domain has yet to be elucidated. Mutation of the MIDAS or LIMBS completely blocked collagen binding to alpha2beta1; in contrast mutation of the ADMIDAS reduced ligand recognition but this effect could be overcome by the activating monoclonal antibody TS2/16. Hence, the MIDAS and LIMBS appear to be essential for the interaction between alphaI and betaI, whereas occupancy of the ADMIDAS has an allosteric effect on the conformation of betaI. An activating mutation in the alpha2 I domain partially restored ligand binding to the MIDAS and LIMBS mutants. Analysis of the effects of Ca(2+), Mg(2+), and Mn(2+) on ligand binding to these mutants showed that the MIDAS is a ligand-competent site through which Mn(2+) stimulates ligand binding, whereas the LIMBS is a stimulatory Ca(2+)-binding site, occupancy of which increases the affinity of Mg(2+) for the MIDAS.

Bhuvaneshwari Mahalingam - One of the best experts on this subject based on the ideXlab platform.

  • stable coordination of the inhibitory ca2 ion at the metal ion dependent adhesion site in integrin cd11b cd18 by an antibody derived ligand aspartate implications for integrin regulation and structure based drug design
    Journal of Immunology, 2011
    Co-Authors: Bhuvaneshwari Mahalingam, Jian-ping Xiong, Kaouther Ajroud, Jose Luis Alonso, Saurabh Anand, Brian D Adair, Alberto L Horenstein, Fabio Malavasi, Amin M Arnaout
    Abstract:

    A central feature of integrin interaction with physiologic ligands is the monodentate binding of a ligand carboxylate to a Mg2+ ion hexacoordinated at the metal ion-dependent adhesion site (MIDAS) in the integrin A domain. This interaction stabilizes the A domain in the high-affinity state, which is distinguished from the default low-affinity state by tertiary changes in the domain that culminate in cell adhesion. Small molecule ligand-mimetic integrin antagonists act as partial agonists, eliciting similar activating conformational changes in the A domain, which has contributed to paradoxical adhesion and increased patient mortality in large clinical trials. As with other ligand-mimetic integrin antagonists, the function-blocking mAb 107 binds MIDAS of integrin CD11b/CD18 A domain (CD11bA), but in contrast, it favors the inhibitory Ca2+ ion over the Mg2+ ion at MIDAS. We determined the crystal structures of the Fab fragment of mAb 107 complexed to the low- and high-affinity states of CD11bA. Favored binding of the Ca2+ ion at MIDAS is caused by the unusual symmetric bidentate ligation of a Fab-derived ligand Asp to a heptacoordinated MIDAS Ca2+ ion. Binding of the Fab fragment of mAb 107 to CD11bA did not trigger the activating tertiary changes in the domain or in the full-length integrin. These data show that the denticity of the ligand Asp/Glu can modify the divalent cation selectivity at MIDAS and hence integrin function. Stabilizing the Ca2+ ion at MIDAS by bidentate ligation to a ligand Asp/Glu may provide one approach for designing pure integrin antagonists.

  • stable coordination of the inhibitory ca 2 ion at the metal ion dependent adhesion site in integrin cd11b cd18 by an antibody derived ligand aspartate implications for integrin regulation and structure based drug design
    Journal of Immunology, 2011
    Co-Authors: Bhuvaneshwari Mahalingam, Jian-ping Xiong, Kaouther Ajroud, Jose Luis Alonso, Saurabh Anand, Brian D Adair, Alberto L Horenstein, Fabio Malavasi, Amin M Arnaout
    Abstract:

    A central feature of integrin interaction with physiologic ligands is the monodentate binding of a ligand carboxylate to a Mg 2+ ion hexacoordinated at the metal ion-dependent adhesion site (MIDAS) in the integrin A domain. This interaction stabilizes the A domain in the high-affinity state, which is distinguished from the default low-affinity state by tertiary changes in the domain that culminate in cell adhesion. Small molecule ligand-mimetic integrin antagonists act as partial agonists, eliciting similar activating conformational changes in the A domain, which has contributed to paradoxical adhesion and increased patient mortality in large clinical trials. As with other ligand-mimetic integrin antagonists, the function-blocking mAb 107 binds MIDAS of integrin CD11b/CD18 A domain (CD11bA), but in contrast, it favors the inhibitory Ca 2+ ion over the Mg 2+ ion at MIDAS. We determined the crystal structures of the Fab fragment of mAb 107 complexed to the low- and high-affinity states of CD11bA. Favored binding of the Ca 2+ ion at MIDAS is caused by the unusual symmetric bidentate ligation of a Fab-derived ligand Asp to a heptacoordinated MIDAS Ca 2+ ion. Binding of the Fab fragment of mAb 107 to CD11bA did not trigger the activating tertiary changes in the domain or in the full-length integrin. These data show that the denticity of the ligand Asp/Glu can modify the divalent cation selectivity at MIDAS and hence integrin function. Stabilizing the Ca 2+ ion at MIDAS by bidentate ligation to a ligand Asp/Glu may provide one approach for designing pure integrin antagonists.

Dima Shepelyansky - One of the best experts on this subject based on the ideXlab platform.

  • synchronization mechanism of sharp edges in rings of saturn
    Monthly Notices of the Royal Astronomical Society, 2009
    Co-Authors: Dima Shepelyansky, A. S. Pikovsky, Jurgen Schmidt, F. Spahn
    Abstract:

    We propose a new mechanism which explains the existence of enormously sharp edges in the rings of Saturn. This mechanism is based on the synchronization phenomenon due to which the epicycle rotational phases of particles in the ring, under certain conditions, become synchronized with the phase of external satellite, e.g. with the phase of Mimas in the case of the outer B ring edge. This synchronization eliminates collisions between particles and suppresses the diffusion induced by collisions by orders of magnitude. The minimum of the diffusion is reached at the centre of the synchronization regime corresponding to the ratio 2:1 between the orbital frequency at the edge of B ring and the orbital frequency of Mimas. The synchronization theory gives the sharpness of the edge in a few tens of meters that is in agreement with available observations.

  • Synchronization mechanism of sharp edges in rings of Saturn
    Monthly Notices of the Royal Astronomical Society, 2009
    Co-Authors: Dima Shepelyansky, A. S. Pikovsky, Julien Schmidt, F. Spahn
    Abstract:

    We propose a new mechanism which explains the existence of enormously sharp edges in the rings of Saturn. This mechanism is based on the synchronization phenomenon due to which the epicycle rotational phases of particles in the ring, under certain conditions, become synchronized with the phase of external satellite, e.g. with the phase of Mimas in the case of the outer B ring edge. This synchronization eliminates collisions between particles and suppress the diffusion induced by collisions by orders of magnitude. The minimum of the diffusion is reached at the center of the synchronization regime corresponding to the ratio 2:1 between the orbital frequency at the edge of B ring and the orbital frequency of Mimas. The synchronization theory gives the sharpness of the edge in few tens of meters that is in agreement with available observations.