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SV2C 人蛋白受体复合物中肉毒神经毒素 A2 的晶体结构揭示了受体结合的柔韧性。

Crystal Structure of Botulinum Neurotoxin A2 in Complex with the Human Protein Receptor SV2C Reveals Plasticity in Receptor Binding.

机构信息

Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden.

Department of Urology, Boston Children's Hospital, Department of Microbiology and Immunobiology and Department of Surgery, Harvard Medical School, Boston, MA 02115, USA.

出版信息

Toxins (Basel). 2018 Apr 12;10(4):153. doi: 10.3390/toxins10040153.

DOI:10.3390/toxins10040153
PMID:29649119
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5923319/
Abstract

Botulinum neurotoxins (BoNTs) are a family of highly dangerous bacterial toxins, with seven major serotypes (BoNT/A-G). Members of BoNTs, BoNT/A1 and BoNT/B1, have been utilized to treat an increasing number of medical conditions. The clinical trials are ongoing for BoNT/A2, another subtype of BoNT/A, which showed promising therapeutic properties. Both BoNT/A1 and BoNT/A2 utilize three isoforms of synaptic vesicle protein SV2 (SV2A, B, and C) as their protein receptors. We here present a high resolution (2.0 Å) co-crystal structure of the BoNT/A2 receptor-binding domain in complex with the human SV2C luminal domain. The structure is similar to previously reported BoNT/A-SV2C complexes, but a shift of the receptor-binding segment in BoNT/A2 rotates SV2C in two dimensions giving insight into the dynamic behavior of the interaction. Small differences in key residues at the binding interface may influence the binding to different SV2 isoforms, which may contribute to the differences between BoNT/A1 and BoNT/A2 observed in the clinic.

摘要

肉毒神经毒素（BoNTs）是一类极具危险性的细菌毒素，包含 7 种主要血清型（BoNT/A-G）。BoNTs 的成员 BoNT/A1 和 BoNT/B1 已被用于治疗越来越多的医疗状况。BoNT/A2 是 BoNT/A 的另一种亚型，其具有有前景的治疗特性，正在进行临床试验。BoNT/A1 和 BoNT/A2 均利用突触小泡蛋白 SV2 的三种同工型（SV2A、B 和 C）作为其蛋白受体。我们在此展示了 BoNT/A2 受体结合域与人类 SV2C 腔结构域复合物的高分辨率（2.0 Å）共晶结构。该结构与先前报道的 BoNT/A-SV2C 复合物相似，但 BoNT/A2 中的受体结合片段的移位使 SV2C 在二维空间中旋转，深入了解了相互作用的动态行为。结合界面上关键残基的微小差异可能会影响与不同 SV2 同工型的结合，这可能有助于解释临床上观察到的 BoNT/A1 和 BoNT/A2 之间的差异。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5f1/5923319/d78dd2c462ef/toxins-10-00153-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5f1/5923319/7f9415e5425e/toxins-10-00153-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5f1/5923319/143575f1268b/toxins-10-00153-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5f1/5923319/4f2b952e5f9d/toxins-10-00153-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5f1/5923319/04a3901628f8/toxins-10-00153-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5f1/5923319/1a5bfe5b2c26/toxins-10-00153-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5f1/5923319/d78dd2c462ef/toxins-10-00153-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5f1/5923319/7f9415e5425e/toxins-10-00153-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5f1/5923319/143575f1268b/toxins-10-00153-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5f1/5923319/4f2b952e5f9d/toxins-10-00153-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5f1/5923319/04a3901628f8/toxins-10-00153-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5f1/5923319/1a5bfe5b2c26/toxins-10-00153-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5f1/5923319/d78dd2c462ef/toxins-10-00153-g006.jpg

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