7Y4A

Crystal structure of human ELMO1 RBD-RhoG complex

Summary for 7Y4A

• Entry DOI: 10.2210/pdb7y4a/pdb
• Descriptor: Rho-related GTP-binding protein RhoG, Engulfment and cell motility protein 1, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: ras binding domain, gtpase, effector, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 124285.08

Authors

Tsuda, K.,Kukimoto-Niino, M.,Shirouzu, M. (deposition date: 2022-06-14, release date: 2023-03-15, Last modification date: 2023-11-29)

Primary citation

Tam, C.,Kukimoto-Niino, M.,Miyata-Yabuki, Y.,Tsuda, K.,Mishima-Tsumagari, C.,Ihara, K.,Inoue, M.,Yonemochi, M.,Hanada, K.,Matsumoto, T.,Shirouzu, M.,Zhang, K.Y.J.
Targeting Ras-binding domain of ELMO1 by computational nanobody design.
Commun Biol, 6:284-284, 2023

PubMed Abstract: The control of cell movement through manipulation of cytoskeletal structure has therapeutic prospects notably in the development of novel anti-metastatic drugs. In this study, we determine the structure of Ras-binding domain (RBD) of ELMO1, a protein involved in cytoskeletal regulation, both alone and in complex with the activator RhoG and verify its targetability through computational nanobody design. Using our dock-and-design approach optimized with native-like initial pose selection, we obtain Nb01, a detectable binder from scratch in the first-round design. An affinity maturation step guided by structure-activity relationship at the interface generates 23 Nb01 sequence variants and 17 of them show enhanced binding to ELMO1-RBD and are modeled to form major spatial overlaps with RhoG. The best binder, Nb29, inhibited ELMO1-RBD/RhoG interaction. Molecular dynamics simulation of the flexibility of CDR2 and CDR3 of Nb29 reveal the design of stabilizing mutations at the CDR-framework junctions potentially confers the affinity enhancement.

PubMed: 36932164
DOI: 10.1038/s42003-023-04657-w

Experimental method

X-RAY DIFFRACTION (1.6 Å)