The Cav family of voltage-gated calcium channels is central to human physiology, however, to date there is limited information on their three-dimensional (3D) structures. Molecular modeling can often improve complex experimental structural data sets of such difficult-to-resolve proteins to the point of accurate 3-dimensional structural models. These 3D models can be a starting point for revealing structure-activity relationships and mechanisms. We describe the development of a novel 3D model metric that enables modeling of the 3D structures of voltage-gated ion channels (VGIC) to an accuracy equivalent to atomic detail experimental resolution. Our metric uses the contact area of a conserved structural motif found in the voltage-sensing-domain of the pore-forming alpha-1 (α1) subunit of the channels as: 1) a measure of model accuracy, 2) landmarks for modeling constraints, 3) a score to rank the accuracy of all deposited structures of VGIC and 4) as a guide to correct inaccuracies found in deposited structural models. Incorporating our metric into homology modeling of the human Cav family of channels provided 3D structures of sufficient accuracy to reveal new structure-activity-relationships (SAR) between sites and experimental, mechanistic and clinical phenotypes. Specifically, we found: a) that the Cav family conserves the structural architecture of the selectivity filter described for the voltage-gated sodium channel family, b) that many Mendelian mutations targeting members of the family are related, as defined under a structural context, and c) that the T-type channel Cav3.1 may have some level of mimicry to Ro60, possibly implicating the channel in the disease known as Congenital Heart Block (CHB). The modeling techniques here described serve as starting points for establishing SAR’s between 3D structural sites and human diseases.
|Advisor:||Cardozo, Timothy J.|
|Commitee:||Stokes, David L., Samuels, Herbert H., Fishman, Glenn I.|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 81/2(E), Dissertation Abstracts International|
|Subjects:||Pharmacology, Bioinformatics, Biophysics|
|Keywords:||Autoimmunity, Channelopathies, Molecular modeling, Structure-activity-relationships, Voltage-gated calcium channels|
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