6YW1

HIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with 2OG and RaPID-derived silent allosteric cyclic peptide 3C (14-mer)

Summary for 6YW1

• Entry DOI: 10.2210/pdb6yw1/pdb
• Related: 5L9B 5L9R 5L9V
• Descriptor: Egl nine homolog 1, PHD2-SPECIFIC RaPID CYCLIC PEPTIDE 3C (14-MER), MANGANESE (II) ION, ... (6 entities in total)
• Functional Keywords: oxidoreductase, non-heme dioxygenase, iron, 2-oxoglutarate, hypoxia-inducible factor, hif, hif prolyl hydroxylase domain 2, phd2, egln1, oxygenase, hypoxia, dna-binding, metal-binding, transcription, helix-loop-helix-beta, dsbh, facial triad, cytoplasm, transcription/epigenetic regulation, signaling, development, cell structure, beta-hydroxylation, transcription activator/inhibitor, ubl conjugation, polymorphism, vitamin c, zinc-finger, familial erythrocytosis, breast cancer, transcription complex
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 28099.68

Authors

Chowdhury, R.,Schofield, C.J. (deposition date: 2020-04-29, release date: 2020-12-30, Last modification date: 2024-01-24)

Primary citation

Chowdhury, R.,Abboud, M.I.,McAllister, T.E.,Banerji, B.,Bhushan, B.,Sorensen, J.L.,Kawamura, A.,Schofield, C.J.
Use of cyclic peptides to induce crystallization: case study with prolyl hydroxylase domain 2.
Sci Rep, 10:21964-21964, 2020

PubMed Abstract: Crystallization is the bottleneck in macromolecular crystallography; even when a protein crystallises, crystal packing often influences ligand-binding and protein-protein interaction interfaces, which are the key points of interest for functional and drug discovery studies. The human hypoxia-inducible factor prolyl hydroxylase 2 (PHD2) readily crystallises as a homotrimer, but with a sterically blocked active site. We explored strategies aimed at altering PHD2 crystal packing by protein modification and molecules that bind at its active site and elsewhere. Following the observation that, despite weak inhibition/binding in solution, succinamic acid derivatives readily enable PHD2 crystallization, we explored methods to induce crystallization without active site binding. Cyclic peptides obtained via mRNA display bind PHD2 tightly away from the active site. They efficiently enable PHD2 crystallization in different forms, both with/without substrates, apparently by promoting oligomerization involving binding to the C-terminal region. Although our work involves a specific case study, together with those of others, the results suggest that mRNA display-derived cyclic peptides may be useful in challenging protein crystallization cases.

PubMed: 33319810
DOI: 10.1038/s41598-020-76307-8

Experimental method

X-RAY DIFFRACTION (1.46 Å)