6WI3
Histone deacetylases complex with peptide macrocycles
Summary for 6WI3
| Entry DOI | 10.2210/pdb6wi3/pdb |
| Descriptor | Histone deacetylase 2, (SHA)W(DTH)DN(DSN)(DME)(DAS)K peptide macrocycle, ZINC ION, ... (8 entities in total) |
| Functional Keywords | anchor extension, de novo design macrocycles, histone deacetylases, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 6 |
| Total formula weight | 137081.78 |
| Authors | Bera, A.K.,Hosseinzadeh, P.,Watson, P.,Baker, D. (deposition date: 2020-04-08, release date: 2021-04-21, Last modification date: 2024-11-13) |
| Primary citation | Hosseinzadeh, P.,Watson, P.R.,Craven, T.W.,Li, X.,Rettie, S.,Pardo-Avila, F.,Bera, A.K.,Mulligan, V.K.,Lu, P.,Ford, A.S.,Weitzner, B.D.,Stewart, L.J.,Moyer, A.P.,Di Piazza, M.,Whalen, J.G.,Greisen, P.J.,Christianson, D.W.,Baker, D. Anchor extension: a structure-guided approach to design cyclic peptides targeting enzyme active sites. Nat Commun, 12:3384-3384, 2021 Cited by PubMed Abstract: Despite recent success in computational design of structured cyclic peptides, de novo design of cyclic peptides that bind to any protein functional site remains difficult. To address this challenge, we develop a computational "anchor extension" methodology for targeting protein interfaces by extending a peptide chain around a non-canonical amino acid residue anchor. To test our approach using a well characterized model system, we design cyclic peptides that inhibit histone deacetylases 2 and 6 (HDAC2 and HDAC6) with enhanced potency compared to the original anchor (IC values of 9.1 and 4.4 nM for the best binders compared to 5.4 and 0.6 µM for the anchor, respectively). The HDAC6 inhibitor is among the most potent reported so far. These results highlight the potential for de novo design of high-affinity protein-peptide interfaces, as well as the challenges that remain. PubMed: 34099674DOI: 10.1038/s41467-021-23609-8 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.35 Å) |
Structure validation
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