Structural Studies of Inositol 1,4,5-Trisphosphate Receptor
Bibliographic record
Abstract
The three isoforms of the inositol 1,4,5-trisphosphate receptor (IP3R) exhibit distinct IP3 sensitivities and cooperativities in calcium (Ca2+) channel function. The determinants underlying this isoform-specific channel gating mechanism have been localized to the N-terminal suppressor region of IP3R. We determined the 1.9 Å crystal structure of the suppressor domain from type 3 IP3R (IP3R3SUP, amino acids 1–224) and revealed structural features contributing to isoform-specific functionality of IP3R by comparing it with our previously determined structure of the type 1 suppressor domain (IP3R1SUP). The molecular surface known to associate with the ligand binding domain (amino acids 224–604) showed marked differences between IP3R3SUP and IP3R1SUP. Our NMR and biochemical studies showed that three spatially clustered residues (Glu-20, Tyr-167, and Ser-217 in IP3R1 and Glu-19, Trp-168, and Ser-218 in IP3R3) within the N-terminal suppressor domains of IP3R1SUP and IP3R3SUP interact directly with their respective C-terminal fragments. Together with the accompanying paper (Yamazaki, H., Chan, J., Ikura, M., Michikawa, T., and Mikoshiba, K. (2010) J. Biol. Chem. 285, 36081–36091), we demonstrate that the single aromatic residue in this region (Tyr-167 in IP3R1 and Trp-168 in IP3R3) plays a critical role in the coupling between ligand binding and channel gating. The three isoforms of the inositol 1,4,5-trisphosphate receptor (IP3R) exhibit distinct IP3 sensitivities and cooperativities in calcium (Ca2+) channel function. The determinants underlying this isoform-specific channel gating mechanism have been localized to the N-terminal suppressor region of IP3R. We determined the 1.9 Å crystal structure of the suppressor domain from type 3 IP3R (IP3R3SUP, amino acids 1–224) and revealed structural features contributing to isoform-specific functionality of IP3R by comparing it with our previously determined structure of the type 1 suppressor domain (IP3R1SUP). The molecular surface known to associate with the ligand binding domain (amino acids 224–604) showed marked differences between IP3R3SUP and IP3R1SUP. Our NMR and biochemical studies showed that three spatially clustered residues (Glu-20, Tyr-167, and Ser-217 in IP3R1 and Glu-19, Trp-168, and Ser-218 in IP3R3) within the N-terminal suppressor domains of IP3R1SUP and IP3R3SUP interact directly with their respective C-terminal fragments. Together with the accompanying paper (Yamazaki, H., Chan, J., Ikura, M., Michikawa, T., and Mikoshiba, K. (2010) J. Biol. Chem. 285, 36081–36091), we demonstrate that the single aromatic residue in this region (Tyr-167 in IP3R1 and Trp-168 in IP3R3) plays a critical role in the coupling between ligand binding and channel gating.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".