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Its protein core is composed of 11 leucine-rich repeats (LRR) flanked by cysteine-rich domains. CHAD makes important interactions with collagen as well as with cell-surface heparin sulfate proteoglycans and \u03b1<jats:sub>2<\/jats:sub>\u03b2<jats:sub>1<\/jats:sub>integrins. The integrin-binding site is located in a region of hitherto unknown structure at the C-terminal end of CHAD. Peptides based on the C-terminal human CHAD (hCHAD) sequence have shown therapeutic potential for treating osteoporosis. This article describes a still-unconventional structure solution by phasing with<jats:italic>de novo<\/jats:italic>models, the first of a \u03b2-rich protein. Structure determination of hCHAD using traditional, though nonsystematic, molecular replacement was unsuccessful in the hands of the authors, possibly owing to a combination of low sequence identity to other LRR proteins, four copies in the asymmetric unit and weak translational pseudosymmetry. However, it was possible to solve the structure by generating a large number of<jats:italic>de novo<\/jats:italic>models for the central LRR domain using<jats:italic>Rosetta<\/jats:italic>and multiple parallel molecular-replacement attempts using<jats:italic>AMPLE<\/jats:italic>. The hCHAD structure reveals an ordered C-terminal domain belonging to the LRRCT fold, with the integrin-binding motif (WLEAK) being part of a regular \u03b1-helix, and suggests ways in which experimental therapeutic peptides can be improved. The crystal structure itself and docking simulations further support that hCHAD dimers form in a similar manner to other matrix LRR proteins.<\/jats:p>","DOI":"10.1107\/s205979831601980x","type":"journal-article","created":{"date-parts":[[2016,12,22]],"date-time":"2016-12-22T17:45:51Z","timestamp":1482428751000},"page":"53-63","update-policy":"https:\/\/doi.org\/10.1107\/cm_01","source":"Crossref","is-referenced-by-count":10,"title":["Crystal structure of human chondroadherin: solving a difficult molecular-replacement problem using<i>de novo<\/i>models"],"prefix":"10.1107","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1801-4983","authenticated-orcid":true,"given":"Sebastian","family":"R\u00e4misch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Pramhed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2869-9477","authenticated-orcid":true,"given":"Viveka","family":"Tillgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6588-6944","authenticated-orcid":true,"given":"Anders","family":"Aspberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0098-8560","authenticated-orcid":true,"given":"Derek T.","family":"Logan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"329","published-online":{"date-parts":[[2017,1,1]]},"reference":[{"key":"kw5133_bb1","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.matbio.2014.05.008","volume":"38","author":"Batista","year":"2014","journal-title":"Matrix Biol."},{"key":"kw5133_bb2","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1107\/S0907444912039194","volume":"68","author":"Bibby","year":"2012","journal-title":"Acta Cryst. 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