The L-type voltage gated calcium channel CaV1.2 is expressed in smooth and cardiac muscle, as well as in neurons where it regulates neuronal excitability and synaptic transmission. Mutations that disrupt channel regulation are linked to various disorders including cardiac arrythmia, Timothy’s Syndrome and epilepsy. Calmodulin (CaM) and calcium-binding protein 1 (CaBP1) are both key modulators of CaV1.2 activity. Under basal resting conditions (cytosolic Ca2+ concentration equal to 100 nM), both CaM and CaBP1 promote channel opening. Under high calcium conditions (cytosolic Ca2+ concentration greater than 1 M), Ca2+-bound CaBP1 further activates the channel in a process called calcium dependent facilitation (CDF); whereas Ca2+-saturated CaM deactivates the channel upon influx of calcium in a process termed calcium dependent inactivation (CDI). Calcium-free calmodulin (apo-CaM) was previously proposed to bind to CaV1.2 and promote channel activation under low calcium conditions, in contrast Ca2+-saturated CaM (4Ca2+-bound CaM) acts as a channel deactivator under high calcium conditions. After analyzing channel electrophysiology and in-vitro binding data as well as nuclear magnetic resonance (NMR) spectra, I conclude that a half-calcified form of CaM (with the C-terminal lobe bound to Ca2+ and the N-terminal lobe devoid of Ca2+, called Ca2/CaM12) is present under basal conditions and is likely responsible for basal channel activation. I used NMR to solve the structure of Ca2/CaM12 complexed with a peptide fragment of the channel, known as the IQ motif (residues 1646-1665). The NMR spectrum of Ca2/CaM12 bound to the IQ peptide structure reveals that the calcium-bound CaM C-terminal lobe interacts with the IQ peptide and the calcium-free CaM N-terminal lobe does not contact the IQ. Based on the structure, I identified hydrophobic residues on CaM (residues A89, F93, V109, M110, L113, M125, and M146) and the IQ motif (I1654, Y1657, and F1658) that are important for the binding interaction. The IQ mutations (I1654A, Y1657D and F1658D) each significantly weakened IQ binding to CaM as measured by isothermal titration calorimetry (ITC) and fluorescence polarization. Additionally, these IQ mutations decrease the CaV1.2 channel open probability determined by electrophysiology analysis (performed in collaboration with Prof Johannes Hell), demonstrating that this binding interaction is important for the basal channel activation. The IQ mutations also prevent CaV1.2 channel inactivation under high calcium conditions and abolish CDI. The results suggests that half-calcified CaM binding to the IQ serves two functional roles: (1) to promote channel activation under basal conditions and (2) to enable channel pre-association with CaM that is essential for rapid channel inactivation during CDI. Our new model is contrary to a previously proposed model in which apo-CaM was suggested to activate the CaV1.2 channel. This earlier model involving apoCaM is inconsistent with our finding that the CaV1.2 mutant K1662E (that disables apoCaM binding to CaV1.2) has no effect on channel open probability. Also, co-expression of CaV1.2 with CaM1234 mutant (that disables Ca2+ binding) in HEK293 cells abolishes basal channel activation in contrast to the 300% increase in channel open probability that occurs when CaV1.2 is co-expressed with wild type CaM. Calcium-binding protein 1 (CaBP1) shares high sequence similarity (56%) to CaM; however, the two EF-hands in the N-lobe of CaBP1 have mutations in the binding loop that prevent Ca2+-binding. This lack of Ca2+ binding to the N-lobe makes CaBP1 a functional analog of half-calcified CaM. Indeed, the calcified C-lobe of CaBP1 binds to the IQ motif of CaV1.2 and promotes Ca2+-dependent channel activation (called CDF) and prevents inactivation of the channel (CDI) in the presence of high calcium. On the basis of sequence similarity between CaBP1 and CaM, I was able to generate a structural model of CaBP1 bound to the IQ peptide by docking the crystal structure of CaBP1 to the IQ motif using the HADDOCK protein docking software. I then performed NMR structural studies on the CaBP1 C-terminal lobe bound to the IQ peptide that revealed intermolecular contacts consistent with those of the docked structure and suggested CaBP1 hydrophobic residues (A107, F111, M128, L131, I144, and M165) make close contact with IQ residues (1654, Y1657, and F1658). The CaBP1 mutation I144E and IQ mutations (I1654D, Y1657D, K1662E and F1658) each weaken IQ binding to CaBP1 and validate the structural model. The NMR-derived structural model of Ca2/CaBP1-IQ closely resembles the Ca2/CaM12-IQ structure. Hydrophobic CaBP1 residues I99, A107, F111, M128, L132, V136, I144, V148, M164, and M165 form a hydrophobic pocket that interacts with IQ residues I1654, Y1657, F1658, and F1661. Additionally, IQ residue K1662, forms a salt bridge with CaBP1 residue D140, which may explain why the K1662E mutation causes 4-fold weaker binding to CaBP1. I propose a structural mechanism for Ca2+-dependent facilitation of CaV1.2 promoted by CaBP1 in which Ca2+ binding to the third and fourth EF-hands of CaBP1 are essential for CaV1.2 channel activation and for abolishing CDI by preventing CaM binding. Future electrophysiology studies are needed to test whether a CaBP1 mutant that disables Ca2+ binding to EF3 and EF4 (CaBP134) can both decrease basal channel open probability and abolish CDF.