6WYP
Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 1 (CD1) K330L mutant complexed with SAHA-BPyne
Summary for 6WYP
| Entry DOI | 10.2210/pdb6wyp/pdb |
| Descriptor | Histone deacetylase 6, ZINC ION, POTASSIUM ION, ... (5 entities in total) |
| Functional Keywords | histone deacetylase, hydrolase, metalloprotein |
| Biological source | Danio rerio (Zebrafish) |
| Total number of polymer chains | 1 |
| Total formula weight | 42657.76 |
| Authors | Osko, J.D.,Christianson, D.W. (deposition date: 2020-05-13, release date: 2020-09-02, Last modification date: 2023-10-18) |
| Primary citation | Osko, J.D.,Christianson, D.W. Binding of inhibitors to active-site mutants of CD1, the enigmatic catalytic domain of histone deacetylase 6. Acta Crystallogr.,Sect.F, 76:428-437, 2020 Cited by PubMed Abstract: The zinc hydrolase histone deacetylase 6 (HDAC6) is unique among vertebrate deacetylases in that it contains two catalytic domains, designated CD1 and CD2. Both domains are fully functional as lysine deacetylases in vitro. However, the in vivo function of only the CD2 domain is well defined, whereas that of the CD1 domain is more enigmatic. Three X-ray crystal structures of HDAC6 CD1-inhibitor complexes are now reported to broaden the understanding of affinity determinants in the active site. Notably, cocrystallization with inhibitors was facilitated by using active-site mutants of zebrafish HDAC6 CD1. The first mutant studied, H82F/F202Y HDAC6 CD1, was designed to mimic the active site of human HDAC6 CD1. The structure of its complex with trichostatin A was generally identical to that with the wild-type zebrafish enzyme. The second mutant studied, K330L HDAC6 CD1, was prepared to mimic the active site of HDAC6 CD2. It has previously been demonstrated that this substitution does not perturb inhibitor binding conformations in HDAC6 CD1; here, this mutant facilitated cocrystallization with derivatives of the cancer chemotherapy drug suberoylanilide hydroxamic acid (SAHA). These crystal structures allow the mapping of inhibitor-binding regions in the outer active-site cleft, where one HDAC isozyme typically differs from another. It is expected that these structures will help to guide the structure-based design of inhibitors with selectivity against HDAC6 CD1, which in turn will enable new chemical biology approaches to probe its cellular function. PubMed: 32880591DOI: 10.1107/S2053230X20010250 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.40006356531 Å) |
Structure validation
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