scholarly journals Comparison of Potent Kv1.5 Potassium Channel Inhibitors Reveals the Molecular Basis for Blocking Kinetics and Binding Mode

2007 ◽  
Vol 20 (6) ◽  
pp. 791-800 ◽  
Author(s):  
Nathalie Strutz-Seebohm ◽  
Ilona Gutcher ◽  
Niels Decher ◽  
Klaus Steinmeyer ◽  
Florian Lang ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Molecular Basis ◽  
Binding Mode ◽  
Blocking Kinetics

scholarly journals Structure Basis of Cav1.1 Modulation by Dihydropyridine Compounds

2020 ◽  
Author(s):  
Shuai Gao ◽  
Nieng Yan
Keyword(s):  
Molecular Basis ◽  
Binding Mode ◽  
Structural Elucidation ◽  
High Efficacy ◽  
Voltage Gated ◽  
Structural Perturbation ◽  
Agonistic Effect ◽  
Chiral Specificity ◽  
Detergent Micelles

Abstract1,4-Dihydropyridines (DHP), the most commonly used antihypertensives, function by inhibiting the L-type voltage-gated Ca2+ (Cav) channels. DHP compounds exhibit chirality-specific antagonistic or agonistic effects. Recent structural elucidation of rabbit Cav1.1 bound to an achiral drug nifedipine reveals the general binding mode for DHP drugs, but the molecular basis for chiral specificity remains elusive. Here, we report five cryo-EM structures of nanodisc-embedded Cav1.1 in the presence of the bestselling drug amlodipine, a DHP antagonist (R)-(+)-Bay K8644, and a titration of its agonistic enantiomer (S)-(-)-Bay K8644 at resolutions of 2.9-3.4 Å. The amlodipine-bound structure reveals the molecular basis for the high efficacy of the drug. All structures with the addition of the Bay K8644 enantiomers exhibit similar inactivated conformations, suggesting that the agonistic effect of (S)-(-)-Bay K8644 might be transient. The similarity of these structures to that obtained in detergent micelles alleviates the concerns about potential structural perturbation by detergents.

Molecular basis of Tityus stigmurus alpha toxin and potassium channel kV1.2 interactions

2019 ◽  
Vol 87 ◽  
pp. 197-203 ◽  
Author(s):  
Marjorie Caroline Liberato Cavalcanti Freire ◽  
Yamara Arruda Silva de Menezes ◽  
Matheus Vitor Ferreira Ferraz ◽  
Carlos Henrique Bezerra da Cruz ◽  
Leandro De Santis Ferreira ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Molecular Basis ◽  
Alpha Toxin

scholarly journals Molecular basis of slow activation of the humanether-á-go-gorelated gene potassium channel

2004 ◽  
Vol 558 (2) ◽  
pp. 417-431 ◽  
Author(s):  
Rajesh N. Subbiah ◽  
Catherine E. Clarke ◽  
David J. Smith ◽  
JingTing Zhao ◽  
Terence J. Campbell ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Molecular Basis

scholarly journals Substrate Binding Mode and Molecular Basis of a Specificity Switch in Oxalate Decarboxylase

Biochemistry ◽  
2016 ◽  
Vol 55 (14) ◽  
pp. 2163-2173 ◽  
Author(s):  
Wen Zhu ◽  
Lindsey M. Easthon ◽  
Laurie A. Reinhardt ◽  
Chingkuang Tu ◽  
Steven E. Cohen ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Substrate Binding ◽  
Binding Mode ◽  
Oxalate Decarboxylase

scholarly journals Structure of Myo7b/USH1C complex suggests a general PDZ domain binding mode by MyTH4-FERM myosins

2017 ◽  
Vol 114 (19) ◽  
pp. E3776-E3785 ◽  
Author(s):  
Jianchao Li ◽  
Yunyun He ◽  
Meredith L. Weck ◽  
Qing Lu ◽  
Matthew J. Tyska ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Common Property ◽  
Pdz Domain ◽  
Binding Mode ◽  
Pdz Domains ◽  
Unconventional Myosin ◽  
Binding Partners ◽  
Interaction Mode ◽  
Similar Mode ◽  
And Function

Unconventional myosin 7a (Myo7a), myosin 7b (Myo7b), and myosin 15a (Myo15a) all contain MyTH4-FERM domains (myosin tail homology 4-band 4.1, ezrin, radixin, moesin; MF) in their cargo binding tails and are essential for the growth and function of microvilli and stereocilia. Numerous mutations have been identified in the MyTH4-FERM tandems of these myosins in patients suffering visual and hearing impairment. Although a number of MF domain binding partners have been identified, the molecular basis of interactions with the C-terminal MF domain (CMF) of these myosins remains poorly understood. Here we report the high-resolution crystal structure of Myo7b CMF in complex with the extended PDZ3 domain of USH1C (a.k.a., Harmonin), revealing a previously uncharacterized interaction mode both for MyTH4-FERM tandems and for PDZ domains. We predicted, based on the structure of the Myo7b CMF/USH1C PDZ3 complex, and verified that Myo7a CMF also binds to USH1C PDZ3 using a similar mode. The structure of the Myo7b CMF/USH1C PDZ complex provides mechanistic explanations for >20 deafness-causing mutations in Myo7a CMF. Taken together, these findings suggest that binding to PDZ domains, such as those from USH1C, PDZD7, and Whirlin, is a common property of CMFs of Myo7a, Myo7b, and Myo15a.

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