6OTN
Crystal Structure of an N-terminal Fragment of Cancer Associated Tropomyosin 3.1 (Tpm3.1)
Summary for 6OTN
| Entry DOI | 10.2210/pdb6otn/pdb |
| Descriptor | Tropomyosin alpha-3 chain, SULFATE ION (3 entities in total) |
| Functional Keywords | tropomyosin, fragment, coiled coil, structural protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 37237.27 |
| Authors | Rynkiewicz, M.J.,Ghosh, A.,Lehman, W.J.,Janco, M.,Gunning, P.W. (deposition date: 2019-05-03, release date: 2019-08-14, Last modification date: 2023-10-11) |
| Primary citation | Janco, M.,Rynkiewicz, M.J.,Li, L.,Hook, J.,Eiffe, E.,Ghosh, A.,Bocking, T.,Lehman, W.J.,Hardeman, E.C.,Gunning, P.W. Molecular integration of the anti-tropomyosin compound ATM-3507 into the coiled coil overlap region of the cancer-associated Tpm3.1. Sci Rep, 9:11262-11262, 2019 Cited by PubMed Abstract: Tropomyosins (Tpm) determine the functional capacity of actin filaments in an isoform-specific manner. The primary isoform in cancer cells is Tpm3.1 and compounds that target Tpm3.1 show promising results as anti-cancer agents both in vivo and in vitro. We have determined the molecular mechanism of interaction of the lead compound ATM-3507 with Tpm3.1-containing actin filaments. When present during co-polymerization of Tpm3.1 with actin, H-ATM-3507 is incorporated into the filaments and saturates at approximately one molecule per Tpm3.1 dimer and with an apparent binding affinity of approximately 2 µM. In contrast, H-ATM-3507 is poorly incorporated into preformed Tpm3.1/actin co-polymers. CD spectroscopy and thermal melts using Tpm3.1 peptides containing the C-terminus, the N-terminus, and a combination of the two forming the overlap junction at the interface of adjacent Tpm3.1 dimers, show that ATM-3507 shifts the melting temperature of the C-terminus and the overlap junction, but not the N-terminus. Molecular dynamic simulation (MDS) analysis predicts that ATM-3507 integrates into the 4-helix coiled coil overlap junction and in doing so, likely changes the lateral movement of Tpm3.1 across the actin surface resulting in an alteration of filament interactions with actin binding proteins and myosin motors, consistent with the cellular impact of ATM-3507. PubMed: 31375704DOI: 10.1038/s41598-019-47592-9 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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