Summary for 6O1G
| Entry DOI | 10.2210/pdb6o1g/pdb |
| Related | 5TZ9 6BFP |
| Descriptor | Plasma kallikrein, 2-acetamido-2-deoxy-beta-D-glucopyranose, N-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-1-({4-[(1H-pyrazol-1-yl)methyl]phenyl}methyl)-1H-pyrazole-4-carboxamide, ... (4 entities in total) |
| Functional Keywords | protease, blood clotting |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 72310.52 |
| Authors | Partridge, J.R.,Choy, R.M. (deposition date: 2019-02-19, release date: 2019-03-06, Last modification date: 2024-10-16) |
| Primary citation | Partridge, J.R.,Choy, R.M.,Silva-Garcia, A.,Yu, C.,Li, Z.,Sham, H.,Metcalf, B. Structures of full-length plasma kallikrein bound to highly specific inhibitors describe a new mode of targeted inhibition. J.Struct.Biol., 206:170-182, 2019 Cited by PubMed Abstract: Plasma kallikrein (pKal) is a serine protease responsible for cleaving high-molecular-weight kininogen to produce the pro-inflammatory peptide, bradykinin. Unregulated pKal activity can lead to hereditary angioedema (HAE) following excess bradykinin release. HAE attacks can lead to a compromised airway that can be life threatening. As there are limited agents for prophylaxis of HAE attacks, there is a high unmet need for a therapeutic agent for regulating pKal with a high degree of specificity. Here we present crystal structures of both full-length and the protease domain of pKal, bound to two very distinct classes of small-molecule inhibitors: compound 1, and BCX4161. Both inhibitors demonstrate low nM inhibitory potency for pKal and varying specificity for related serine proteases. Compound 1 utilizes a surprising mode of interaction and upon binding results in a rearrangement of the binding pocket. Co-crystal structures of pKal describes why this class of small-molecule inhibitor is potent. Lack of conservation in surrounding residues explains the ∼10,000-fold specificity over structurally similar proteases, as shown by in vitro protease inhibition data. Structural information, combined with biochemical and enzymatic analyses, provides a novel scaffold for the design of targeted oral small molecule inhibitors of pKal for treatment of HAE and other diseases resulting from unregulated plasma kallikrein activity. PubMed: 30876891DOI: 10.1016/j.jsb.2019.03.001 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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