5jpn
Structure of human complement C4 rebuilt using iMDFF
Structural highlights
DiseaseCO4A_HUMAN Defects in C4A are the cause of complement component 4A deficiency (C4AD) [MIM:614380. A rare defect of the complement classical pathway associated with the development of autoimmune disorders, mainly systemic lupus with or without associated glomerulonephritis.[1] Defects in C4A are a cause of susceptibility to systemic lupus erythematosus (SLE) [MIM:152700. A chronic, inflammatory and often febrile multisystemic disorder of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. It is thought to represent a failure of the regulatory mechanisms of the autoimmune system. Note=Interindividual copy-number variation (CNV) of complement component C4 and associated polymorphisms result in different susceptibilities to SLE. The risk of SLE susceptibility has been shown to be significantly increased among subjects with only two copies of total C4. A high copy number is a protective factor against SLE.[2] FunctionCO4A_HUMAN C4 plays a central role in the activation of the classical pathway of the complement system. It is processed by activated C1 which removes from the alpha chain the C4a anaphylatoxin. The remaining alpha chain fragment C4b is the major activation product and is an essential subunit of the C3 convertase (C4b2a) and the C5 convertase (C3bC4b2a) enzymes of the classical complement pathway. Derived from proteolytic degradation of complement C4, C4a anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes. Publication Abstract from PubMedWhile the rapid proliferation of high-resolution structures in the Protein Data Bank provides a rich set of templates for starting models, it remains the case that a great many structures both past and present are built at least in part by hand-threading through low-resolution and/or weak electron density. With current model-building tools this task can be challenging, and the de facto standard for acceptable error rates (in the form of atomic clashes and unfavourable backbone and side-chain conformations) in structures based on data with dmax not exceeding 3.5 A reflects this. When combined with other factors such as model bias, these residual errors can conspire to make more serious errors in the protein fold difficult or impossible to detect. The three recently published 3.6-4.2 A resolution structures of complement C4 (PDB entries 4fxg, 4fxk and 4xam) rank in the top quartile of structures of comparable resolution both in terms of Rfree and MolProbity score, yet, as shown here, contain register errors in six beta-strands. By applying a molecular-dynamics force field that explicitly models interatomic forces and hence excludes most physically impossible conformations, the recently developed interactive molecular-dynamics flexible fitting (iMDFF) approach significantly reduces the complexity of the conformational space to be searched during manual rebuilding. This substantially improves the rate of detection and correction of register errors, and allows user-guided model building in maps with a resolution lower than 3.5 A to converge to solutions with a stereochemical quality comparable to atomic resolution structures. Here, iMDFF has been used to individually correct and re-refine these three structures to MolProbity scores of <1.7, and strategies for working with such challenging data sets are suggested. Notably, the improved model allowed the resolution for complement C4b to be extended from 4.2 to 3.5 A as demonstrated by paired refinement. Re-evaluation of low-resolution crystal structures via interactive molecular-dynamics flexible fitting (iMDFF): a case study in complement C4.,Croll TI, Andersen GR Acta Crystallogr D Struct Biol. 2016 Sep;72(Pt 9):1006-16. doi:, 10.1107/S2059798316012201. Epub 2016 Aug 18. PMID:27599733[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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