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Title: Solving the structure of Lgl2, a difficult blind test of unsupervised structure determination

Abstract

In the companion paper by Ufimtsev and Levitt [Ufimtsev IS, Levitt M (2019) Proc Natl Acad Sci USA, 10.1073/pnas.1821512116], we presented a method for unsupervised solution of protein crystal structures and demonstrated its utility by solving several test cases of known structure in the 2.9- to 3.45-Å resolution range. Here we apply this method to solve the crystal structure of a 966-amino acid construct of human lethal giant larvae protein (Lgl2) that resisted years of structure determination efforts, at 3.2-Å resolution. The structure was determined starting with a molecular replacement (MR) model identified by unsupervised refinement of a pool of 50 candidate MR models. This initial model had 2.8-Å RMSD from the solution. The solved structure was validated by comparison with a model subsequently derived from an alternative crystal form diffracting to higher resolution. This model could phase an anomalous difference Fourier map from an Hg derivative, and a single-wavelength anomalous dispersion phased density map made from these sites aligned with the refined structure.

Authors:
ORCiD logo [1];  [1];  [1]; ORCiD logo [1]
  1. Stanford Univ. School of Medicine, Stanford, CA (United States)
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1532382
Grant/Contract Number:  
AC02-76SF00515
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 116; Journal Issue: 22; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Ufimtsev, Ivan S., Almagor, Lior, Weis, William I., and Levitt, Michael. Solving the structure of Lgl2, a difficult blind test of unsupervised structure determination. United States: N. p., 2019. Web. doi:10.1073/pnas.1821513116.
Ufimtsev, Ivan S., Almagor, Lior, Weis, William I., & Levitt, Michael. Solving the structure of Lgl2, a difficult blind test of unsupervised structure determination. United States. doi:10.1073/pnas.1821513116.
Ufimtsev, Ivan S., Almagor, Lior, Weis, William I., and Levitt, Michael. Tue . "Solving the structure of Lgl2, a difficult blind test of unsupervised structure determination". United States. doi:10.1073/pnas.1821513116. https://www.osti.gov/servlets/purl/1532382.
@article{osti_1532382,
title = {Solving the structure of Lgl2, a difficult blind test of unsupervised structure determination},
author = {Ufimtsev, Ivan S. and Almagor, Lior and Weis, William I. and Levitt, Michael},
abstractNote = {In the companion paper by Ufimtsev and Levitt [Ufimtsev IS, Levitt M (2019)Proc Natl Acad Sci USA, 10.1073/pnas.1821512116], we presented a method for unsupervised solution of protein crystal structures and demonstrated its utility by solving several test cases of known structure in the 2.9- to 3.45-Å resolution range. Here we apply this method to solve the crystal structure of a 966-amino acid construct of human lethal giant larvae protein (Lgl2) that resisted years of structure determination efforts, at 3.2-Å resolution. The structure was determined starting with a molecular replacement (MR) model identified by unsupervised refinement of a pool of 50 candidate MR models. This initial model had 2.8-Å RMSD from the solution. The solved structure was validated by comparison with a model subsequently derived from an alternative crystal form diffracting to higher resolution. This model could phase an anomalous difference Fourier map from an Hg derivative, and a single-wavelength anomalous dispersion phased density map made from these sites aligned with the refined structure.},
doi = {10.1073/pnas.1821513116},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 22,
volume = 116,
place = {United States},
year = {2019},
month = {5}
}

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