QM/MM model of the mouse olfactory receptor MOR244-3 validated by site-directed mutagenesis experiments

Sivakumar Sekharan; Mehmed Z Ertem; Hanyi Zhuang; Eric Block; Hiroaki Matsunami; Ruina Zhang; Jennifer N Wei; Yi Pan; Victor S Batista

doi:10.1016/j.bpj.2014.07.031

QM/MM model of the mouse olfactory receptor MOR244-3 validated by site-directed mutagenesis experiments

Biophys J. 2014 Sep 2;107(5):L5-L8. doi: 10.1016/j.bpj.2014.07.031.

Authors

Sivakumar Sekharan¹, Mehmed Z Ertem², Hanyi Zhuang³, Eric Block⁴, Hiroaki Matsunami⁵, Ruina Zhang⁶, Jennifer N Wei⁷, Yi Pan⁶, Victor S Batista⁸

Affiliations

¹ Department of Chemistry, Yale University, New Haven, Connecticut. Electronic address: sivakumar.sekharan@yale.edu.
² Department of Chemistry, Yale University, New Haven, Connecticut; Chemistry Department, Brookhaven National Laboratory, Upton, New York. Electronic address: mzertem@bnl.gov.
³ Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China; Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine/Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences, Shanghai, P. R. China. Electronic address: hanyizhuang@sjtu.edu.cn.
⁴ Department of Chemistry, University at Albany, State University of New York, Albany, New York.
⁵ Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina; Department of Neurobiology, Duke University Medical Center, Durham, North Carolina.
⁶ Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.
⁷ Department of Chemistry, Yale University, New Haven, Connecticut.
⁸ Department of Chemistry, Yale University, New Haven, Connecticut. Electronic address: victor.batista@yale.edu.

Abstract

Understanding structure/function relationships of olfactory receptors is challenging due to the lack of x-ray structural models. Here, we introduce a QM/MM model of the mouse olfactory receptor MOR244-3, responsive to organosulfur odorants such as (methylthio)methanethiol. The binding site consists of a copper ion bound to the heteroatoms of amino-acid residues H105, C109, and N202. The model is consistent with site-directed mutagenesis experiments and biochemical measurements of the receptor activation, and thus provides a valuable framework for further studies of the sense of smell at the molecular level.

Publication types

Letter
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Validation Study

MeSH terms

Animals
Binding Sites
Computer Simulation
Copper / chemistry
Humans
Ions / chemistry
Mice
Models, Molecular
Molecular Sequence Data
Mutagenesis, Site-Directed
Protein Structure, Secondary
Quantum Theory
Receptor, Muscarinic M2 / chemistry
Receptors, Odorant / chemistry*
Receptors, Odorant / genetics
Sequence Alignment
Structure-Activity Relationship
Water / chemistry

Substances

Ions
MOR244-3 protein, mouse
Olfr256 protein, mouse
Receptor, Muscarinic M2
Receptors, Odorant
Water
Copper

Abstract

Publication types

MeSH terms

Substances

Grants and funding