5MT4
COMPLEMENT FACTOR D IN COMPLEX WITH A REVERSIBLE BENZOIC ACID BASED INHIBITOR
Summary for 5MT4
| Entry DOI | 10.2210/pdb5mt4/pdb |
| Descriptor | Complement factor D, 2-[(phenylmethyl)carbamoylamino]benzoic acid (3 entities in total) |
| Functional Keywords | hydrolase |
| Biological source | Homo sapiens (Human) |
| Cellular location | Secreted: P00746 |
| Total number of polymer chains | 1 |
| Total formula weight | 25009.40 |
| Authors | Mac Sweeney, A.,Ostermann, N. (deposition date: 2017-01-06, release date: 2017-02-15, Last modification date: 2024-10-23) |
| Primary citation | Vulpetti, A.,Randl, S.,Rudisser, S.,Ostermann, N.,Erbel, P.,Mac Sweeney, A.,Zoller, T.,Salem, B.,Gerhartz, B.,Cumin, F.,Hommel, U.,Dalvit, C.,Lorthiois, E.,Maibaum, J. Structure-Based Library Design and Fragment Screening for the Identification of Reversible Complement Factor D Protease Inhibitors. J. Med. Chem., 60:1946-1958, 2017 Cited by PubMed Abstract: Chronic dysregulation of alternative complement pathway activation has been associated with diverse clinical disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinurea. Factor D is a trypsin-like serine protease with a narrow specificity for arginine in the P1 position, which catalyzes the first enzymatic reaction of the amplification loop of the alternative pathway. In this article, we describe two hit finding approaches leading to the discovery of new chemical matter for this pivotal protease of the complement system: in silico active site mapping for hot spot identification to guide rational structure-based design and NMR screening of focused and diverse fragment libraries. The wealth of information gathered by these complementary approaches enabled the identification of ligands binding to different subpockets of the latent Factor D conformation and was instrumental for understanding the binding requirements for the generation of the first known potent noncovalent reversible Factor D inhibitors. PubMed: 28157311DOI: 10.1021/acs.jmedchem.6b01684 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.65 Å) |
Structure validation
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