Matthew T. Geballe
Emory University
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Matthew T. Geballe.
Molecular Pharmacology | 2007
Kevin Erreger; Matthew T. Geballe; Anders Kristensen; Philip E. Chen; Kasper B. Hansen; C. Justin Lee; Hongjie Yuan; Phuong Thi Quy Le; Polina Lyuboslavsky; Nicola Micale; Lars N. Jorgensen; Rasmus P. Clausen; David J. A. Wyllie; James P. Snyder; Stephen F. Traynelis
The four N-methyl-d-aspartate (NMDA) receptor NR2 subunits (NR2A-D) have different developmental, anatomical, and functional profiles that allow them to serve different roles in normal and neuropathological situations. Identification of subunit-selective NMDA receptor agonists, antagonists, or modulators could prove to be both valuable pharmacological tools as well as potential new therapeutic agents. We evaluated the potency and efficacy of a wide range of glutamate-like compounds at NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D receptors. Twenty-five of 53 compounds examined exhibited agonist activity at the glutamate binding site of NMDA receptors. Concentration-response relationships were determined for these agonists at each NR2 subunit. We find consistently higher potency at the NR2D subunit for a wide range of dissimilar structures, with (2S,4R)-4-methylglutamate (SYM2081) showing the greatest differential potency between NR2A- and NR2D-containing receptors (46-fold). Analysis of chimeric NR2A/D receptors suggests that enhanced agonist potency for NR2D is controlled by residues in both of the domains (Domain1 and Domain2) that compose the bilobed agonist binding domain. Molecular dynamics (MD) simulations comparing a crystallography-based hydrated NR1/NR2A model with a homology-based NR1/NR2D hydrated model of the agonist binding domains suggest that glutamate exhibits a different binding mode in NR2D compared with NR2A that accommodates a 4-methyl substitution in SYM2081. Mutagenesis of functionally divergent residues supports the conclusions drawn based on the modeling studies. Despite high homology and conserved atomic contact residues within the agonist binding pocket of NR2A and NR2D, glutamate adopts a different binding orientation that could be exploited for the development of subunit selective agonists and competitive antagonists.
The Journal of Neuroscience | 2010
Shashank M. Dravid; Pieter B. Burger; Anand Prakash; Matthew T. Geballe; Roopali Yadav; Phuong Thi Quy Le; Kimberly Vellano; James P. Snyder; Stephen F. Traynelis
We have studied relative efficacies of NR1 agonists glycine and d-cycloserine (DCS), and found efficacy to be dependent on the NR2 subunit. DCS shows partial agonism at NR1/NR2B but has higher relative efficacy than glycine at NR1/NR2C receptor. Molecular dynamics (MD) simulations of the NR1/NR2B and NR1/NR2C agonist binding domain dimer suggest only subtle differences in the interactions of DCS with NR1 binding site residues relative to glycine. The most pronounced differences were observed in the NR1/NR2C simulation between the orientation of helices F and G of the NR1 subunit. Interestingly, Helix F was previously proposed to influence receptor gating and to adopt an orientation depending on agonist efficacy. MD simulations and site-directed mutagenesis further suggest a role for residues at the agonist binding domain dimer interface in regulating DCS efficacy. To relate the structural rearrangements to receptor gating, we recorded single-channel currents from outside-out patches containing a single active NR1/NR2C receptor. DCS increased the mean open time and open probability of NR1/NR2C receptors compared with glycine. Maximum likelihood fitting of a gating model for NR1/NR2C receptor activation to the single-channel data suggests that DCS specifically accelerates the rate constant governing a fast gating step and reduces the closing rate. These changes appear to reflect a decreased activation energy for a pregating step and increased stability of the open states. We suggest that the higher efficacy of DCS at NR1/NR2C receptors involves structural rearrangements at the dimer interface and an effect on NR1/NR2C receptor pregating conformational changes.
The Journal of Physiology | 2008
Philip E. Chen; Matthew T. Geballe; Elyse Katz; Kevin Erreger; Matthew R. Livesey; Kate K. O'Toole; Phuong Thi Quy Le; C. Justin Lee; James P. Snyder; Stephen F. Traynelis; David J. A. Wyllie
Heteromeric NMDARs are composed of coagonist glycine‐binding NR1 subunits and glutamate‐binding NR2 subunits. The majority of functional NMDARs in the mammalian central nervous system (CNS) contain two NR1 subunits and two NR2 subunits of which there are four types (A–D). We show that the potency of a variety of endogenous and synthetic glycine‐site coagonists varies between recombinant NMDARs such that the highest potency is seen at NR2D‐containing and the lowest at NR2A‐containing NMDARs. This heterogeneity is specified by the particular NR2 subunit within the NMDAR complex since the glycine‐binding NR1 subunit is common to all NMDARs investigated. To identify the molecular determinants responsible for this heterogeneity, we generated chimeric NR2A/2D subunits where we exchanged the S1 and S2 regions that form the ligand‐binding domains and coexpressed these with NR1 subunits in Xenopus laevis oocytes. Glycine concentration–response curves for NMDARs containing NR2A subunits including the NR2D S1 region gave mean glycine EC50 values similar to NR2A(WT)‐containing NMDARs. However, receptors containing NR2A subunits including the NR2D S2 region or both NR2D S1 and S2 regions gave glycine potencies similar to those seen in NR2D(WT)‐containing NMDARs. In particular, two residues in the S2 region of the NR2A subunit (Lys719 and Tyr735) when mutated to the corresponding residues found in the NR2D subunit influence glycine potency. We conclude that the variation in glycine potency is caused by interactions between the NR1 and NR2 ligand‐binding domains that occur following agonist binding and which may be involved in the initial conformation changes that determine channel gating.
The Journal of Neuroscience | 2005
Kevin Erreger; Matthew T. Geballe; Shashank M. Dravid; James P. Snyder; David J. A. Wyllie; Stephen F. Traynelis
The NMDA ionotropic glutamate receptor is ubiquitous in mammalian central neurons. Because partial agonists bind to the same site as glutamate but induce less channel activation, these compounds provide an opportunity to probe the mechanism of activation of NMDA-type glutamate receptors. Molecular dynamics simulations and site-directed mutagenesis demonstrate that the partial agonist homoquinolinate interacts differently with binding pocket residues than glutamate. Homoquinolinate and glutamate induce distinct changes in the binding pocket, and the binding pocket exhibits significantly more motion with homoquinolinate bound than with glutamate. Patch-clamp recording demonstrates that single-channel activity induced by glutamate or by homoquinolinate has identical single-channel current amplitude and mean open-channel duration but that homoquinolinate slows activation of channel opening relative to glutamate. We hypothesize that agonist-induced conformational changes in the binding pocket control the efficacy of a subunit-specific activation step that precedes the concerted global change in the receptor-channel complex associated with ion channel opening.
Archive | 2008
Hongjie Yuan; Matthew T. Geballe; Kasper B. Hansen; Stephen F. Traynelis
1 Ionotropic glutamate receptors are ligand-gated ion channels that mediate excitatory synaptic transmission in the central nervous system. Based on their structural and pharmacological properties, ionotropic glutamate receptors can be divided into three groups, which include α-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid (AMPA) receptors, kainate receptors, and N-methyl-D-aspartate (NMDA) receptors. Historically, these groups were named on the basis of the activating agonist. AMPA and kainate receptors are discussed in the chapter by Mayer. NMDA receptors are distinguished from other ionotropic glutamate receptors by their unique features including requirement for simultaneous binding of the co-agonists glycine and glu- tamate, voltage-dependent Mg 2+ block, and high permeability to Ca 2+ . NMDA recep- tors contribute to the slow component of the excitatory postsynaptic current (EPSC) and play key roles in neuronal development, synaptic plasticity, learning, and mem- ory, as well as in a number of pathophysiological conditions including epilepsy, and Alzheimers disease), and psychiatric disorders (e.g. schizophrenia). Therefore, understanding the relationship between structure and function of the NMDA receptor will provide valuable insights into the mechanisms of synaptic transmission, as well as pathophysiology of a number of disorders in the central nervous system. Under- standing this relationship will also facilitate the development of therapeutically use- ful compounds.
Journal of Biological Chemistry | 2009
Hongjie Yuan; Katie M. Vance; Candice E. Junge; Matthew T. Geballe; James P. Snyder; John R. Hepler; Manuel Yepes; Chian-Ming Low; Stephen F. Traynelis
Zinc is hypothesized to be co-released with glutamate at synapses of the central nervous system. Zinc binds to NR1/NR2A N-methyl-d-aspartate (NMDA) receptors with high affinity and inhibits NMDAR function in a voltage-independent manner. The serine protease plasmin can cleave a number of substrates, including protease-activated receptors, and may play an important role in several disorders of the central nervous system, including ischemia and spinal cord injury. Here, we demonstrate that plasmin can cleave the native NR2A amino-terminal domain (NR2AATD), removing the functional high affinity Zn2+ binding site. Plasmin also cleaves recombinant NR2AATD at lysine 317 (Lys317), thereby producing a ∼40-kDa fragment, consistent with plasmin-induced NR2A cleavage fragments observed in rat brain membrane preparations. A homology model of the NR2AATD predicts that Lys317 is near the surface of the protein and is accessible to plasmin. Recombinant expression of NR2A with an amino-terminal deletion at Lys317 is functional and Zn2+ insensitive. Whole cell voltage-clamp recordings show that Zn2+ inhibition of agonist-evoked NMDA receptor currents of NR1/NR2A-transfected HEK 293 cells and cultured cortical neurons is significantly reduced by plasmin treatment. Mutating the plasmin cleavage site Lys317 on NR2A to alanine blocks the effect of plasmin on Zn2+ inhibition. The relief of Zn2+ inhibition by plasmin occurs in PAR1-/- cortical neurons and thus is independent of interaction with protease-activated receptors. These results suggest that plasmin can directly interact with NMDA receptors, and plasmin may increase NMDA receptor responses through disruption or removal of the amino-terminal domain and relief of Zn2+ inhibition.
Molecular Pharmacology | 2012
Pieter B. Burger; Hongjie Yuan; Erkan Karakas; Matthew T. Geballe; Hiro Furukawa; Dennis C. Liotta; James P. Snyder; Stephen F. Traynelis
We have used recent structural advances in our understanding of the N-methyl-d-aspartate (NMDA) receptor amino terminal domain to explore the binding mode of multiple diaryl GluN2B-selective negative allosteric modulators at the interface between the GluN1 and GluN2B amino-terminal domains. We found that interaction of the A ring within the binding pocket seems largely invariant for a variety of structurally distinct ligands. In addition, a range of structurally diverse linkers between the two aryl rings can be accommodated by the binding site, providing a potential opportunity to tune interactions with the ligand binding pocket via changes in hydrogen bond donors, acceptors, as well as stereochemistry. The most diversity in atomic interactions between protein and ligand occur in the B ring, with functional groups that contain electron donors and acceptors providing additional atomic contacts within the pocket. A cluster of residues distant to the binding site also control ligand potency, the degree of inhibition, and show ligand-induced increases in motion during molecular dynamics simulations. Mutations at some of these residues seem to distinguish between structurally distinct ligands and raise the possibility that GluN2B-selective ligands can be divided into multiple classes. These results should help facilitate the development of well tolerated GluN2B subunit-selective antagonists.
Molecular Brain | 2008
Fui-Mee Ng; Matthew T. Geballe; James P. Snyder; Stephen F. Traynelis; Chian-Ming Low
BackgroundPhenylethanolamines selectively bind to NR2B subunit-containing N-methyl-D-aspartate-subtype of ionotropic glutamate receptors and negatively modulate receptor activity. To investigate the structural and functional properties of the ifenprodil binding domain on the NR2B protein, we have purified a soluble recombinant rat NR2B protein fragment comprising the first ~400 amino acid amino-terminal domain (ATD2B) expressed in E. coli. Spectral measurements on refolded ATD2B protein demonstrated specific binding to ifenprodil. We have used site-directed mutagenesis, circular dichroism spectroscopy and molecular modeling to obtain structural information on the interactions between critical amino acid residues and ifenprodil of our soluble refolded ATD2B proteins. Ligand-induced changes in protein structure were inferred from changes in the circular dichroism spectrum, and the concentration dependence of these changes was used to determine binding constants for ifenprodil and its analogues.ResultsLigand binding of ifenprodil, RO25,6981 and haloperidol on soluble recombinant ATD2B determined from circular dichroism spectroscopy yielded low-to-high micromolar equilibrium constants which concurred with functional IC50 measurement determined in heterologously expressed NR1/NR2B receptors in Xenopus oocytes. Amino acid residue substitutions of Asp101, Ile150 and Phe176 with alanine residue within the ATD2B protein altered the recombinant protein dissociation constants for ifenprodil, mirroring the pattern of their functional phenotypes. Molecular modeling of ATD2B as a clam-shell-like structure places these critical residues near a putative ligand binding site.ConclusionWe report for the first time biochemical measurements show that the functional measurements actually reflect binding to the ATD of NR2B subunit. Insights gained from this study help advance the theory that ifenprodil is a ligand for the ATD of NR2B subunit.
Journal of Medicinal Chemistry | 2008
Yesim Altas Tahirovic; Matthew T. Geballe; Ewa Gruszecka-Kowalik; Scott J. Myers; Polina Lyuboslavsky; Phuong Thi Quy Le; Adam French; Hasan Irier; Woo-Baeg Choi; Keith Easterling; Hongjie Yuan; Lawrence J. Wilson; Robert Kotloski; James O McNamara; Raymond Dingledine; Dennis C. Liotta; Stephen F. Traynelis; James P. Snyder
Enantiomeric propanolamines have been identified as a new class of NR2B-selective NMDA receptor antagonists. The most effective agents are biaryl structures, synthesized in six steps with overall yields ranging from 11-64%. The compounds are potent and selective inhibitors of NR2B-containing recombinant NMDA receptors with IC 50 values between 30-100 nM. Potency is strongly controlled by substitution on both rings and the centrally located amine nitrogen. SAR analysis suggests that well-balanced polarity and chain-length factors provide the greatest inhibitory potency. Structural comparisons based on 3D shape analysis and electrostatic complementarity support this conclusion. The antagonists are neuroprotective in both in vitro and in vivo models of ischemic cell death. In addition, some compounds exhibit anticonvulsant properties. Unlike earlier generation NMDA receptor antagonists and some NR2B-selective antagonists, the present series of propanolamines does not cause increased locomotion in rodents. Thus, the NR2B-selective antagonists exhibit a range of therapeutically interesting properties.
ChemBioChem | 2009
Andrew Prussia; Yutao Yang; Matthew T. Geballe; James P. Snyder
Cyclostreptin (CS) is a recently discovered natural product with cytotoxic activity caused by microtubule stabilization. It is the only known microtubule‐stabilizing agent (MSA) that covalently binds to tubulin. It also exhibits the fast‐binding kinetics seen for other MSAs. Through careful peptide digestion and mass spectrometry analysis, Buey et al. found that two amino acids are labeled by CS: Asn228, near the known taxane‐binding site, and Thr220, in the type I microtubule pore. This led Buey et al. to propose Thr220 resides at the site previously predicted to be a way station or low‐affinity site. By using molecular dynamics simulations and structural considerations of the microtubule pore and tubulin dimer, we conclude that postulation of a low‐affinity site is unnecessary to explain the available experimental data. An alternative explanation views the microtubule pore as a structural entity that presents a substantial kinetic barrier to ligand passage to the known taxane‐binding site—an entry point to the microtubule lumen that becomes completely blocked if cyclostreptin is bound at Thr220. Simulations of the free dimer also suggest a common mechanism of microtubule stabilization for taxane site MSAs through their conformational effect on the M‐loop. Such an effect explains the low tubulin polymerization caused by cyclostreptin in vitro despite its covalent attachment.